European Journal of Preventive Cardiology http://cpr.sagepub.com/

Inflammation modulation and cardiovascular disease prevention Zuhier Awan and Jacques Genest European Journal of Preventive Cardiology published online 7 April 2014 DOI: 10.1177/2047487314529350 The online version of this article can be found at: http://cpr.sagepub.com/content/early/2014/04/07/2047487314529350

Published by: http://www.sagepublications.com

On behalf of: European Society of Cardiology

European Association for Cardiovascular Prevention and Rehabilitation

Additional services and information for European Journal of Preventive Cardiology can be found at: Email Alerts: http://cpr.sagepub.com/cgi/alerts Subscriptions: http://cpr.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav

>> OnlineFirst Version of Record - Apr 7, 2014 What is This?

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

EURO PEAN SO CIETY O F CARDIOLOGY ®

Original scientific paper

Inflammation modulation and cardiovascular disease prevention Zuhier Awan1 and Jacques Genest2

European Journal of Preventive Cardiology 0(00) 1–15 ! The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487314529350 ejpc.sagepub.com

Abstract Heart disease and stroke represent the major burden of health worldwide and account for a staggering 17 million deaths yearly. This pandemic is, in great part preventable through simple and modifiable preventive measures such as smoking cessation, healthy eating, regular activity and weight loss. In patients with established atherosclerotic vascular disease, lipid lowering agent have had a major impact on reducing risk, along with pharmacological treatment of elevated blood pressure and the use of anti-thrombotic medication. Despite these advances, there remains a significant residual risk and newer approaches are required to decrease atherosclerosis. Innate and acquired immunity play a pivotal role in the initiation, progression and instability of the atherosclerotic plaque. The remarkable complexity of the immune system makes it difficult to target a single pathway for the prevention of cardiovascular disease. Nevertheless, recent data points to possible therapeutic targets that may decrease atherosclerosis, without increasing the risk of infection, decreasing immune surveillance for cancers and without undue toxicity. Here we discuss the clinical trials and registry data associated with the use of inflammation modulation and cardiovascular disease and the ongoing major clinical trial that may change the clinical medicine and preventive cardiology. The selective inhibition of interleukin 1b and the use of low-dose methotrexate are now undergoing large outcome-driven clinical trials to answer these questions.

Keywords CVD, cardiovascular disease, prevention, inflammation, immunomodulation Received 10 March 2014; accepted 4 March 2014

Introduction Cardiovascular disease continues to represent the major burden of mortality and morbidity in the developed world and is rapidly becoming the major health issue in emerging market economies. Worldwide an estimated 17 million deaths due to cardiovascular diseases occurred in 2008, with the majority being due to atherosclerotic cardiovascular disease.1,2 It is anticipated that this number will increase to more than 20 million in the present decade. The INTERHEART study has shown that acute myocardial infarction (MI) due to coronary artery disease can be explained by conventional cardiovascular risk factors (in addition to the non-modifiable risk factors of male gender and increasing age), that include smoking, dyslipidemias (as reflected by apolipoproteins (apos), the ratio apoB/ apoAI reflecting atherogenic lipoproteins and high-density lipoproteins respectively), hypertension, diabetes, obesity, diet, physical activity, alcohol consumption and psychosocial stress. Overall, these account for over 90% of the attributed risk of acute MI. These

risk factors were contiuous, graded and coherent across all populations studied.3 Perhaps not surprisingly, the odds ratio for MI were highest for the apoB/AI ratio, reflecting recent data from the Emerging Risk Factor Collaboration showing that apoB (or non-high density lipoprotein (non-HDL)-C) as a measure of atherogenic lipoproteins and highdensity lipoprotein (HDL)-C (or apoAI) are strongly associated with cardiovascular disease.4 Of the modifiable risk factors, smoking cessation has had a major impact on public health, with a decrease in MI rates in communities where smoking has been decreased. The treatment of high blood pressure has been shown, 1 2

King Abdulaziz University, Saudi Arabia Research Institute, McGill University Health Centre, Canada

Corresponding author: Jacques Genest, Faculty of Medicine, McGill University Health Centre/ Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC, H3A-1A1, Canada. Email: [email protected]

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

2

European Journal of Preventive Cardiology 0(00)

in meta-analysis to also reduce MI and coronary artery disease (CAD)-related death, but to a lesser degree than a reduction in strokes.5 Diabetes control, as determined by glucose levels or by glycosylated hemoglobin measurement (HbA1c) has had much less of an impact than previously thought and, individually, trials that aimed at reaching a lower HbA1c failed to show a significant beneficial effect on mortality and morbidity at low levels of HbA1c. This prompted a re-evaluation of recommendations for patients with diabetes patients and the focus is now on vascular protection, tight blood pressure control, lowering of low-density lipoprotein (LDL)-C and reaching an HbA1c level of 6.5–7.0% in order to decrease microvascular disease and for a long-term impact on macro-vascular disease. The treatment of obesity has been one of the most challenging aspects of cardiovascular prevention. The development of the ‘‘cardiometabolic syndrome’’ associated with obesity represents one of the greatest challenges to health globally. While all societies recommend weight reduction and physical activity, even the best programs are difficult to sustain over a long period of time.6 The treatment of lipoprotein disorders has been one of the most successful therapeutic measures in the prevention and treatment of cardiovascular disease worldwide and strict targets for LDL-C are mandated in international guidelines.7,8 The analysis of large-scale clinical trials using inhibitors of hydroxylmethylglutaryl coenzyme A (‘‘statins’’) have led to an impressive decrease in cardiovascular events, cardiovascular mortality and total mortality, with no evidence of major side effects. The reduction of cardiovascular disease appears to be dose and duration-related to treatment.9 A new class of lipid lowering agents, the proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have the potential to further lower LDL-C. PCSK9 is one of the serine proteases that bind to LDL receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. In several reports, targeting this protein with monoclonal antibody in phase I and II studies has significantly reduced LDL cholesterol levels in healthy volunteers and subjects with familial or nonfamilial hypercholesterolemia.10 Large-scale phase III clinical trials are underway to test the hypothesis that further LDL-C lowering with PCSK9 inhibitors will further improve cardiovascular health. Unfortunately, there is little evidence that raising HDL-C pharmacologically with fibrates,11 niacin12,13 or two inhibitors of cholesteryl ester transfer protein, torcetrapib and dalcetrapib, leads to a reduction of CAD. Using Mendelian randomization, the causal relationship between HDL-C and CAD or MI has recently been put into question.14,15 It is possible that the measurement of HDLC represents a bio-marker of cardiovascular health and not necessarily a causal risk factor.

Despite the impressive results obtained with statins, there remains an appreciable ‘‘residual risk’’ in the prevention and treatment of atherosclerotic cardiovascular diseases. Overall, statin trials have shown a 20–30% reduction in risk.16 The search for other modifiable factors has led to novel targets in the atherosclerosis process. A review of available clinical data has determined that chronic inflammatory diseases status put a patient in a higher category to develop cardiovascular disease; although much of the data is largely based on small studies. However further research consisting of prospective cohort studies are needed to better quantify this risk.17 Inflammation is critical to the development of atherosclerosis. While conventional cardiovascular risk factors such as elevated cholesterol are causal in atherosclerosis, the mechanism by which cholesterol induces atherosclerosis is mediated, in great part via the immune system. Elegant studies by Duewell et al.18 and Rajama¨ki et al.19 have shown that microcrystals of cholesterol are taken up by macrophages and elicit an inflammatory reaction through the activation of the NOD-like receptor, pyrin domain containing-3 (NLRP3) inflammasome with subsequent release of IL-1b, leading to an amplifying cascade of immune response.20 Interleukin (IL)-1b and IL-6 together with other systemic inflammatory mediators such as tumor necrosis factor-alpha (TNFa) are released in the circulation, leading to hepatic production of C-reactive protein (CRP).21 The strong association between CRP, a marker of systemic inflammation, and cardiovascular disease has been tested in multiple epidemiological studies and meta-analysis show that high sensitivity (hs) CRP is a graded and independent biomarker of cardiovascular risk. The causal link between CRP and atherosclerosis has been put into question by animal studies which do not suggest a pro-atherosclerosis role for CRP and Mendelian randomization experiments that have cast doubt on whether CRP has a causal role in atherosclerosis. This point is still a matter of debate.22 Nevertheless, the ability of hsCRP to identify a subset of patients at increased cardiovascular risk, and especially to identify a group of patients with a high risk of recurrent cardiovascular events is the basis of the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. In JUPITER, 17,801 men >50 years and women >60 years with an elevated CRP but a level of LDL-C that did not warrant lipidlowering therapy, according to the standard of care at the time, were randomized to rosuvastatin 20 mg or placebo. After two years on trial, the data and safety monitoring Board recommended that the study be stopped because of the overwhelming benefit in the rosuvastatin-treated patients. On rosuvastatin, patients

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

Awan and Genest

3

had a 50% decrease in LDL-C and a 37% reduction in hsCRP, leading to a 44% reduction in the combined primary end point of MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.23 This was reflected in several national guidelines as an entity to consider more aggressive lipid lowering regiment.7,8 However the results of JUPITER led to the question whether the benefits of rosuvastatin were due solely to the reduction in LDL-C or the reduction in CRP had a beneficial effect as well. The trial was not designed to answer this apparently simple question, but offered a novel hypothesis that can be tested in large-scale, appropriate clinical trials.

Chronic inflammation and atherosclerotic cardiovascular diseases The pathogenesis of atherosclerosis is complex and beyond the scope of this review.24 Atherosclerotic plaques may stabilize and even regress in response to statins and become less susceptible to rupture. Calcified plaques, however, may not show much evidence of regression and the calcification process is intimately linked to inflammation.25 Arterial inflammation in response to stressors (elevated cholesterol, shear stress due to elevated blood pressure, cigarette-derived vascular toxins, protein modification by diabetes-related hyperglycemia lead to endothelial dysfunction and the expression of vascular cell adhesion molecules (VCAMs) and monocyte chemotactic protein-1 (MCP-1) may attract monocytes to the arterial intima, which will differentiate into macrophages and lead to foam cells formation. Complex, vulnerable plaques may rupture and cause thrombosis, leading to blood obstruction in vital organs, such the heart (causing acute coronary syndromes and MI), peripheral blood vessels (causing gangrene) and brain (causing strokes). In the normal intima of aortas, T-cells and macrophages are present and have the capacity to express IL-1, IL-6 and TNF.26 The oxidized LDL particles that intrude into the subendothelial space as a result of endothelial dysfunction are sensed and engulfed by macrophages and may trigger the expression of immune mediators. Under the control of innate immunity, mononuclear phagocytes, mast cells, platelets, granulocytes, and the complement cascade contribute to amplify the immune response and promote the growth of the atherosclerotic plaque.24 In the adaptive cellular immune response T- and B-cells, antigen presenting dendritic cells (DCs) and humoral immunity exert modulatory effects on atherosclerosis. The interplay between human genetic susceptibility and response to environmental stressors modulate adaptive and innate immunity. One of the best known stressors is

elevated cholesterol. Current data implicates cholesterol micro-crystals as being an initiating factor in the release of IL-1b through the activation of the NLRP3 inflammasome.18,19 Inflammasomes are large, cytosolic multimeric protein complexes that connect the metabolic stress sensing with proteolytic cleavage of prointerleukin-1b into bioactive IL-1b (Figure 1). Inflammasomes are thus responsible for activation of inflammatory processes, and have been shown to induce cell pyroptosis.27 It should be noted that several cytokines, especially Il-4, Il-10 and Il-13 may have a protective modulatory effect on vascular inflammation. The finding of human autosomal dominant gain-offunction mutations in the NLRP3 gene associated with the autoinflammatory process has supported the effort to target inhibition of IL-1b as an orphan drug indication.28 The targeted inactivation of IL-1b decreased atherosclerosis in a mouse model of atherosclerosis (apoE–/–/IL-1–/–) fed a high cholesterol diet.29 In addition, lack of IL-1b decreased the severity of atherosclerosis in apoE–/– mice while prolonged treatment with IL-1b promotes arterial intimal thickening in the porcine coronary artery.30 Furthermore IL-1 has been implicated in atherothrombosis and plaque rupture in several pre-clinical and clinical studies.31 IL-1b plays an essential role in triggering an inflammatory response to injury and mediating the smooth muscle cell differentiation via the actions of TNFa on the Wnt (Wg (wingless) and Int1 (integrin 1) genes in drosophila) canonical pathway.27 In addition genetic strategies may work to compliment and close the loop of inflammation causality in humans. Genome-wide association studies (GWAS) and newer deep sequencing data have begun to identify associations between variants in determinants of immune and inflammatory function and atherosclerotic in humans. The more recent CARDIoGRAMplusC4D Consortium GWAS provided a network analysis that implicated inflammation as one of the four pathways most strongly associated with human MI.32 In particular, recent genetic studies provide robust data linking the IL-6 receptor to coronary heart disease.33 These data provides a strong rationale for targeting inflammatory pathways to narrow the gap in cardiovascular disease residual risk.

Early trials of immunomodulation to decrease cardiovascular disease Corticosteroids The finding in patients with asthma that using inhaled corticosteroids (fluticasone) suppresses VCAM-1 expression induced by TNFa during exacerbations of the disease suggested that suppression of epithelial VCAM-1 expression by glucocorticoids may contribute

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

[1–15] [PREPRINTER stage]

(CPR)

4

European Journal of Preventive Cardiology 0(00)

Vascular wall

Arterial media Arterial lumen Smooth muscle cells

Innate immune cell

Endogenous Danger Signal

mAb

Phagolysosome Cytokine

Cholesterol crystals

NLRP3 Inflammasome

Cytokine

LDL Lysosome Oxidized LDL

Phagosome

Atherosclerotic plaque

IL-18

Pro-IL-18

Caspase-1 IL-1b

Systemic inflammation SAA1, CRP

Pro-IL-1b

Liver IL-6

TNFa

IL-1b

mAb

Figure 1. Diagramatic representation of an atherosclerotic plaque and the interplay between micro-cholesterol crystals and innate immunity. CRP: C-reactive protein; IL: interleukin; LDL: low-density lipoprotein; mAb: monoclonal antibodies; NLRP3: NOD-like receptor, pyrin domain containing-3; SAA: serum amyloid A; TNF: tumor necrosis factor.

to their anti-inflammatory effects (at least in human bronchial epithelial cells in humans), but this effect could not be extended to the vascular endothelium.34 In mice, high-dose corticosteroids used post-acute MI were found to exert a level of cardiovascular protection through a novel mechanism involving the rapid, nontranscriptional activation of endothelial nitric oxide synthase. Binding of corticosteroids to the glucocorticoid receptor stimulated phosphatidylinositol 3kinase and protein kinase (Akt), leading to endothelial nitric oxide synthase activation and nitric oxide dependent vasorelaxation in mice leading to decreased vascular inflammation and reduced myocardial infarct size following ischemia and reperfusion injury model.35 However the beneficial long term effect of inhaled corticosteroids was only validated in asthmatic patients and not in cardiovascular patients.36 Despite these interesting results, early reports suggested that corticosteroids may promote atherosclerosis. In the early 1970s, Kalbak et al. predicting the outcome of long term corticosteroid by calcific arteriosclerosis of the tibial artery as seen on X-ray films.37 The incidence of arteriosclerosis in patients with rheumatoid arthritis receiving long-term corticosteroid was elevated and arterial calcification was common and resembles Mo¨nckeberg’s sclerosis type with little

intimal occlusion. Many years later CAD treated by high doses and prolonged courses of corticosteroids was clearly associated with adverse effects on the cardiovascular system in the form of systemic vascular resistance, extracellular volume and incidence of left ventricular wall rupture due to delaying myocardial scar formation in the post-MI period.38 In addition multiple population studies reveal that high-dose glucocorticoids are associated with increased risk for a cardiovascular event.39 A second case-control study linked oral glucocorticoids and heart failure (HF),40 thus a lower dose and an alternate day regiments to lower incidence of complications in corticosteroid therapy was recommended. Finally a nested case-control analysis of 404,183 patients estimated the risk of acute MI associated with the use of oral corticosteroids to be higher in high-dose users.41 Moreover in a systemic inflammation context like systemic lupus erythematosus, aortic valve calcification was associated with prednisone use (p ¼ 0.049) and use of methotrexate (p ¼ 0.0174).42 It was found that rheumatoid factor (RF)-positive and not RFnegative patients are at increased additional risk of CV events following exposure to glucocorticoids. These findings suggest that glucocorticoids interact with RF status to modulate the occurrence of an

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

Awan and Genest

5

event in patients with rheumatoid arthritis (RA).43 A nested case-control analysis of MI in a large cohort of 17,738 patients with RA and 3001 patients with noninflammatory rheumatic found that corticosteroids increased the risk of diabetes and hypertension and contribute to the overall risk of MI.44 A recent study implicated endogenous hypercortisolism with the incidence increased of coronary arterial atherosclerosis as assisted by non-invasive coronary angiography computerized tomography (CT) scan.45 Finally a dose-dependent cardiovascular risk for prednisone long-term use in RA patients put to rest claims for cardiovascular protection potential.46

Methotrexate (MTX) MTX competitively and reversibly binds to dihydrofolate reductase preventing the conversion of tetrahydrofolate precursor to the co-factor necessary for DNA and RNA synthesis arresting the cell in S phase. Methotrexate has been used for decades as an anticancer agent, as an immunomodulator in rheumatological and autoimmune skin diseases and as an agent to terminate ectopic pregnancies. Its narrow therapeutic index and side effect profile makes this agent difficult to use broadly. A systematic review of the effect of methotrexate on cardiovascular disease in patients with RA concluded that use was associated with a reduced risk events suggesting that MTX not only improves disease-specific outcomes but concomitant atherosclerosis.47 Importantly a large study of 10,156 RA patients treated with a variety of TNF antagonists, MTX and other disease-modifying antirheumatic drugs (DMARDs); only TNF antagonists were associated with a reduced in cardiovascular risk events. MTX was not associated with a reduced risk and prednisone use was associated with a dose-dependent increased risk as mentioned above.46 However, both a systematic review and meta-analysis of evidence of relations of methotrexate with cardiovascular disease occurrence were performed in patients with chronic inflammation.48 MTX was associated with a 21% lower risk for total cardiovascular disease; these findings suggest that a direct treatment of inflammation may reduce cardiovascular disease risk. Given its profound effect as a broad immunosuppressant the National Heart, Lung, and Blood Institute (NHLBI) launched the Cardiovascular Inflammation Reduction Trial (CIRT) (http://clinicaltrials.gov - NCT01594333) (see Table 1). This is a randomized clinical trial investigating whether taking low-dose MTX reduces heart attacks, strokes, or death in people with type 2 diabetes or metabolic syndrome that have had a heart attack and the estimated study completion date will be in December 2018.

TNF TNFa or cachectin is a cytokine that induces cytolysis of certain tumors and acts as potent pyrogen causing fever directly or via IL-1b induction. The protein is synthesized as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine.49 Both the mature protein and a partially processed one are secreted in to the blood.50 Many animal studies as well as some initial clinical trials have suggested that downregulation of TNFa may improve cardiac performance. Soluble TNF receptor inhibition negates myocardial inflammation. However, left ventricular wall thickening was not reversed in this cytokine-induced cardiomyopathy model.51 Etanercept or intravenous immunoglobulin attenuated the expression of genes coding for atrial natriuretic peptide (ANP), myosin heavy chains and extracellular matrix in a rat model of MI. This raises the possible early immunomodulatory benefits post-MI to prevent later development of HF.52 Treatment with TNFa blockers was associated with a lower incidence of first cardiovascular events in patients with RA in a retrospective study of 531 patients.53 In ankylosing spondylitis patients the use of TNF inhibitors was thought to stabilize or slow down the progression of subclinical atherosclerosis, reflecting a decreased cardiovascular risk.54 In addition, another large study of 10,156 RA patients treated with a variety of TNF antagonists, methotrexate and other DMARDs; only the TNF antagonists were associated with a reduced in cardiovascular risk events. While MTX was not associated with a reduced risk and prednisone use was associated with a dose-dependent increased risk.46 On the other hand, preliminary results from placebocontrolled anti-TNFa studies suggest no effect, or even an adverse effect of anti-TNFa therapy on mortality and hospitalization. This study was in a three-group setting of RA patients that were randomized to TNFa blockers, MTX and placebo. The finding of elevated levels of soluble TNF-RII and interferon (IFN) g in patients with RA on anti-TNF suggests that this therapy does not completely restrain the inflammatory process and may promote atherogenesis.55 In a cross-sectional and longitudinal study of 23 patients with RA commencing antiTNFa therapy, inflammatory markers were non-superior to classical risk in influencing endothelial function suggesting that combined cardiovascular disease prevention approaches may be necessary.56 In addition following acute MI, etanercept reduces systemic inflammation but increases platelet activation without affecting peripheral vasomotor or fibrinolytic function. In this study the authors concluded that TNFa

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

6

European Journal of Preventive Cardiology 0(00)

Table 1. Ongoing Phase III clinical trials using biologicals to prevent cardiovascular disease

Name of the Study

ClinicalTrials.gov identifier (Phase) Sponsor

CIRT Trial (Cardiovascular Inflammation Reduction Trial)

NCT01594333 (Phase III) NHLBI

Randomized, double-blind, placebocontrolled

Etanercept safety and efficacy treating patients with acute ST-segment elevation MI

NCT01372930 (Phase IV) Xijing Hospital

A study of tocilizumab in comparison to etanercept in patients with RA and cardiovascular risk factors

Primary endpoint and (estimated completion date)

Estimated enrollment

Active agent

Rate of recurrent MACE (completion December 2018)

7000

MTX

Randomized, open-label

Composite of MACE (completion July 2014)

200

TNFa

NCT01331837 (Phase IV) Hoffmann-La Roche

Randomized, openlabel

Occurrence of MACE (completion October 2016)

3080

TNFa/ IL-6

CANTOS Trial Cardiovascular Risk Reduction Study (Reduction in Recurrent Major CV Disease Events)

NCT01327846 (Phase III) Novartis

Randomized, double-blind, placebocontrolled

Time to the first occurrence of MACE (completion July 2016)

17,200

IL-1b

STABILITY Trial The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial

NCT00799903 (Phase III) GlaxoSmithKline

Randomized, double-blind, placebocontrolled

Time to the first occurrence of MACE (completion October 2013)

15,828

Lp-PLA2

SOLIDIFY Trial The Stabilization Of pLaques usIng DarapladibThrombolysis In Myocardial Infarction 52 Trial (SOLIDTIMI 52)

NCT01000727 (Phase III) GlaxoSmithKline

Randomized, double-blind, placebocontrolled

Time to the first occurrence of MACE (completion March 2014)

13,000

Lp-PLA2

Design of the Study

MACE, major adverse cardiovascular events; TIMI, The Thrombolysis in Myocardial Infarction Study Group; NHLBI, National Heart, Lung, and Blood Institute. (Source http://ClinicalTrials.gov accessed November 2013.)

antagonism is unlikely to be a beneficial therapeutic strategy in patients with acute MI.57 Although somewhat disappointing, these negative results do not necessarily argue against the cytokine hypothesis. These studies only underscore the difficulties and challenges in developing treatment modalities that can modulate the cytokine network in patients with inflammation-associated atherosclerosis, resulting in anti-inflammatory and beneficial net effects. The route of TNF inhibition may be indicative of success depending on how fast the vascular bed can be reached. A significant decreased risk in MI was found in psoriasis subjects using the subcutaneous etanercept route compared to treatment with topical agents.58 Currently there is an animal model of K/BxA(g7) mice which recapitulates the same sequence of events occurring in patients with RA, namely an erosive, inflammatory arthritis followed by atherosclerosis. This novel system

may tease out the inflammation component that needs to be dealt with in the development of atherosclerosis without overshooting in the immune system.59 Targeted TNFa inhibitor use may be associated with the development or exacerbation of HF. TNFa antibodies tested in patients with moderate to severe HF did not demonstrate any clinical benefits and this suggests that etanercept may adversely affect the course of the disease.60,61 Concern about this possible adverse effect stems from randomized clinical trials of TNFa inhibitors as a potential therapy for HF and from postmarketing surveillance data gathered by the US Food and Drug Administration (FDA).62 Given the evidence to date, patients with symptomatic HF should be treated with strategies other than TNFa inhibitors. In a patient who develops HF while on a TNFa inhibitor, a druginduced cause should be suspected, and use of the medication should be suspended (see Table 2). Importantly

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

Awan and Genest

7

Table 2. Currently available biologicals under investigation for the prevention of cardiovascular disease and potential adverse events Methotrexate - Rheumatrex - Trexall

Tumor necrosis factor alpha -

Infliximab Adalimumab Golimumab Etanercept (TNFa receptor fusion protein) - Certolizumab (pegylated humanized antibody Fab fragment)

Interleukin-6

Interleukin-1Ra

Interleukin 1-b

- Tocilizumab (mAb directed against IL-6)

- Kineret: Anakinra (IL-1 receptor antagonist):

- Iiaris: Canakinumab* (mAb directed against IL-1b)

(" LDL-C)

(NA)

($ LDL-C)

Injection site, reactions Infections, Malignancy.

Injection site reactions, Infections.

Expected changes in LDL-C with each approach (NA)

(" LDL-C)

Potential adverse events in each immunomodulation approach Bone marrow, suppression, Neutropenia, Infections.

Injection site reactions, Infusion reactions (Acute and delayed), Neutropenia, Infections, Demyelinating disease, Heart failure, Cutaneous reactions, including psoriasis, Malignancy, Induction of autoimmunity.

Injection site reactions, Infusion reactions, Infections, Liver function disorders, Neutropenia, Diarrhea.

TNFa inhibitors have been associated with the development or exacerbation of neurologic disorders associated with demyelination, such as multiple sclerosis. However the true nature of this association has not been established.63 Anti-TNFa therapy should be discontinued immediately in any patient with suspected demyelination. Reported neurologic findings include confusion, ataxia, dysesthesia, facial nerve palsy, hemiparesis, paresthesia, optic neuritis, transverse myelitis, and ascending motor neuropathy. At present, a study is being conducted in patients with recent ST-segment MI (STEMI) using etanercept to determine whether major adverse cardiovascular events (MACEs) are reduced (NCT01372930, http://clinicaltrials.gov) (see Table 1).

IL-6 IL-6 is secreted by macrophages in atherosclerotic plaques as a response to specific antigens, referred to as pathogen-associated molecular patterns. In turn, these bind to a group of detection molecules of the innate immune system termed pattern recognition receptors; including toll-like receptors present on the cell surface which induce cytokine production. In addition, smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as well as adipocytes and this

may explain the reason why obese individuals have higher endogenous levels of CRP.64 IL-6 is a multifunction cytokine responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells. Interestingly, IL-6 can mitigate inflammation through its inhibitory effects on TNFa and IL-1, and activation of interleukin-1 receptor antagonist (IL-1Ra) and IL10.65 In a carotid atherosclerotic model, using perivascular constrictive silica collar, IL-6 was found to destabilize atherosclerotic plaques by downregulating a key intracellular enzyme required for synthesis of collagen.66 Tocilizumab is a humanized anti-human IL-6 receptor antibody; it competes for both the membranebound and the soluble forms of human IL-6 receptor, thereby inhibiting the binding of the native cytokine to its receptor and interfering with the effects of cytokine. Tocilizumab was shown to be effective in improving endothelial dysfunction and reducing arterial stiffness in RA patients.67,68 It is therapeutically effective in patients with RA and in systemic onset juvenile idiopathic arthritis compared with placebo when administered by intravenous infusion every four weeks. Some adverse events such as liver function disorders,

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

8

European Journal of Preventive Cardiology 0(00)

neutropenia, diarrhea, infection and hyperlipidemia are observed in clinical trials (Table 2).69 Drug-induced hyperlipidemia is generally tolerated, however as clinical trials are being conducted, the currently available TNFa inhibitors and IL-6 inhibitors increase LDL, and thus the issue of cardiovascular safety needs to be addressed. Recently, it was reported that IL-6 receptor blockade could be considered in the prevention of coronary heart disease,70 or even be useful for the treatment of acute MI, as suggested in an ongoing study investigating randomized study (NCT01491074, http://clinicaltrials.gov). The effect of the IL-6 receptor antagonist tocilizumab in non-ST elevation MI will be assessed by the primary outcome measurement of hsCRP-Area under the curve and secondary outcome being markers troponin T and pro-brain-type natriuretic peptide (BNP) (see Table 3).

IL-1 Stimulation of the IL-1 receptor on vascular endothelial cells leads to upregulation of inducible nitric oxide synthase (iNOS), endothelin-1, chemokines/cytokines, adhesion molecules, endothelial and smooth muscle proliferation and macrophage activation, processes that contribute to endothelial dysfunction and progression of atherosclerosis.71 Both IL-1a and IL-1b activate IL-1 receptor type I (IL-1R1) to mount proinflammatory status, while the IL-1Ra physiologically and competitively inhibits their binding. IL-1a remains associated with the plasma membrane, whereas IL-1b is fully secreted and can act on IL-1R1 on cells distant from the cell of origin. Thus IL-1b has been thought to be of greater relevance to human inflammatory diseases.

Table 3. Ongoing Phase II clinical trials using biologicals to prevent cardiovascular disease Primary endpoint and (estimated completion date)

ClinicalTrials.gov identifier (Phase) Sponsor

Design of the study

Effect of tocilizumab in non-ST elevation MI

NCT01491074 (Phase II) Oslo University Hospital

Randomized, doubleblind, placebocontrolled

hsCRP AUC (completion not provided)

120

IL-6

VCU-ART3 Trial IL-1 Blockade in Acute Myocardial Infarction

NCT01950299 (Phase II/III) NIH

Randomized, doubleblind, placebocontrolled

hsCRP AUC (completion September 2016)

99

IL-1Ra

CONVERT-AF Trial Canakinumab for the Prevention of Recurrences After Electrical Cardioversion

NCT01805960 (Phase II) Basel University

Randomized double-blind

Recurrence of atrial fibrillation (completion June 2015)

100

IL-1b

Darapladib (SB-480848) In Subjects With Coronary Heart Disease

NCT00269048 (Phase II) GlaxoSmithKline

Randomized, doubleblind, placebocontrolled

Sustained inhibition of plasma Lp-PLA2 activity in Subjects With Stable Coronary Heart Disease (completion not provided)

920

Lp-PLA2

Study to Determine the Effect of 14 Days Dosing With Darapladib (SB480848) on Carotid Plague Composition in Patients With Planned Carotid Endarterectomy

NCT01916720 (Phase II) GlaxoSmithKline

Randomized, doubleblind, placebocontrolled

Lp-PLA2 activity in the atherosclerotic plaque removed during carotid endarterectom (completion not provided)

103

Lp-PLA2

Name of the study

Estimated enrollment

Active agent

hsCRP, high-sensitivity C-reactive protein; AUC, area under the curve; NIH, National Institutes of Health; VCU-ART, Virginia Commonwealth University Anakinra Remodeling Trial. (Source http://ClinicalTrials.gov accessed November 2013.)

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

Awan and Genest

9

IL-1Ra

IL-1

This is a naturally occurring glycoprotein inhibitor which can neutralize the inflammatory effects mediated by IL-1. It is found in both circulating and intracellular isoforms. A synthetic IL-1 receptor antagonist (anakinra) can be used as a biologic DMARD. However it is administered daily due to its short half-life via a subcutaneous injection and acts through competitive binding with IL-1 for its receptor, but with no receptor signaling activation. It exhibits modest clinical efficacy and a dose-dependent increased risk of serious infection in patients with RA compared with placebo. Furthermore IL-1 may also modulate cholesterol plasma levels by serum amyloid A (SAA) induction.72 The ratio of IL-1 to IL-1Ra is critical in vascular inflammation. In obese patients, IL-1Ra levels are increased,73 partly secreted by adipose tissue. In this population, IL-1Ra promotes leptin and insulin resistance and weight gain.73 Thus the effect of the synthetic IL-1 antagonist may be parallel to the development of these conditions. In another trial, MARkers of INfLammation, a randomized, placebo-controlled, multicenter study comparing two-week anakinra therapy to placebo in patients with non-STEMI), recruitment has been completed and the early phase clinical trials in patients with STEMI did not meet their primary goals.74 Ikonomidis et al. reported that anakinra may improve vascular and left ventricular function in patients with RA but without coronary disease.75 This improvement was related to a concomitant reduction in nitro-oxidative stress and endothelin-1 levels. It is not known if results from this non-randomized study may be extrapolated to patients without RA but suffering from coronary disease, which would be more relevant. Nevertheless, a study is evaluating whether anakinra also improves vascular and left ventricular function in patients with coronary diseases and coexistent RA (NCT01566201, http://clinicaltrials.gov) (see Table 4). The serial Virginia Commonwealth University Anakinra Remodeling (VCU-ART) studies (NCT01175018, http://clinicaltrials.gov) reported that anakinra in acute MI assessed in 10 patients was safe and beneficial on left ventricular remodelling.76 The VCU-ART-2 study, again evaluating anakinra to prevent adverse post-infarction remodeling, is presently completed. This study compared anakinra with placebo for the development of HF as assisted by cardiac magnetic resonance in patients with STEMI (NCT01175018, http://clinicaltrials.gov). The recruiting VCU-ART-3 study of standard and high doses will look at the primary outcome measurement of hsCRP, and the estimated study completion date is September 2016 (NCT01950299, http://clinicaltrials.gov) (see Table 3).

The targeted inactivation of IL-1b decreased atherosclerosis in a mouse model of atherosclerosis (apoE–/–/ IL-1–/–) fed a high cholesterol diet.29 In clinical studies, IL-1 concentrations were found in high levels in atherosclerotic human coronary arteries.77 Most importantly IL-1b inhibition modulates a pro-inflammatory mediator that is not essential for host defense or IL-1b signaling critical to innate immunity. There is a relationship between the earliest deposition of cholesterol crystals and the initiation of inflammation, likely through the NLRP3 inflammasome as mentioned above. Reports have shown that IL-1b influences TNF receptor regulation.78,79 Although its biological effects are transduced by binding to an independent receptor, IL-1R1, IL-1b activates similar signaling pathways as TNFa to induce primarily proinflammatory gene expression.80 However, effects of IL-1b on individual TNF receptor expression and shedding are not fully understood. Holtmann and Wallach81 further demonstrated that IL-1b modified TNFa signaling through alterations in TNF receptor mRNA expression. The development of a IL-1b inhibitor was promoted as an orphan drug28 to treat CryopyrinAssociated Periodic Syndromes (CAPS), a genetic variance of NLRP3 gene causing autoinflammatory disorders and approved in 2009 by the European Medicines Agency in London [EMEA/503722/2009]. An extensive program of toxicology studies was performed in marmoset monkeys and conducted with the murine form mAb 01BSUR in mice. Using this surrogate antibody in mice, it was further shown that neutralization of IL-1b does not inhibit the development of a T cell-dependent antibody response induced by immunization in the presence of aluminium hydroxide as adjuvant. Regarding the immune system, there were no differences in counts for total lymphocytes and lymphocyte subsets in the blood, spleen and thymus. Treatment of mouse pups with 01BSUR by once weekly subcutaneous injection for nine weeks resulted in generally minimal inflammatory reactions at the injection sites. These were reversible over a fourweek recovery period. In addition, pharmacokinetics of 01BSUR was determined in mice after single and repeated subcutaneous administration. A dose-dependent increase was observed with a peak approximately 24 h after dosing and the elimination half-life ranged between 1–17 days. Male and female fertility was not affected by treatment nor was reproductive toxicity observed. This leads the way to launching of the CANTOS trial (NCT01327846, http://clinicaltrials. gov) (see Table 1). The primary outcome in CANTOS is the first occurrence of major adverse

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

10

European Journal of Preventive Cardiology 0(00)

Table 4. Ongoing pilot clinical trials using biologicals to prevent cardiovascular disease

Name of the study

ClinicalTrials.gov identifier (Phase) Sponsor

Design of the study

Primary endpoint and (estimated completion date)

Estimated enrollment

Active agent

Escape II Myocardium

NCT01548768 (Not Provided) Columbia University

Randomized, single-blind, safety/efficacy study

Improvement of left ventricular mass and LVEF (completion October 2015)

50

TNFa/Triple therapy*

Effects of TNF-alpha antagonism (Etanercept) in patients with the metabolic syndrome and psoriasis

NCT00477191 (Not Provided) Massachusetts General Hospital

Randomized, single-blind, safety/efficacy study

Effects of etanercept on CRP levels (completion December 2014)

40

TNFa

Cardiovascular effects in psoriasis patients treating with adalimumab

NCT01320293 (Not Provided) University of North Carolina

Single group assignment, open-label, safety/ efficacy study

Percentage change in endothelial function compared to baseline (completion September 2015)

52

TNFa

Pilot feasibility study of the safety and efficacy of anakinra in heart failure (HF) with preserved ejection function

NCT01542502 (Not Provided) Virginia Commonwealth University

Randomized, doubleblind, placebocontrolled

Peak VO2 (completion June 2013)

14

IL-1Ra

Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease

NCT01566201 (Not Provided) University of Athens

Randomized, double-blind

Improvement of vascular and left ventricular function (completion not provided)

80

IL-1Ra

Interleukin-1 Blockade With Canakinumab to Improve Exercise Capacity in Patients With Chronic Systolic Heart Failure and Elevated Hs-CRP

NCT01900600 (Not Provided) Virginia Commonwealth University

Randomized, single-blind, safety/efficacy study

Peak VO2 (completion September 2018)

30

IL-1b

Assessment of Coronary Plaque Composition Using Optical Coherence Tomography

NCT01642173 (Not Provided) GlaxoSmithKline

Single group assignment, open-label, diagnostic evaluation

Quantification of plaque vulnerability (completion August 2015)

80

Lp-PLA2

Lp-PLA2 and Coronary Atherosclerosis in Humans

NCT01557088 (Not Provided) NIH

Single group assignment, open-label, diagnostic evaluation

Three inflammatory measures of the Lp-PLA2 pathway (completion January 2014)

200

Lp-PLA2

*Triple therapy: sulfasalazine þ Methotrexat þ Plaquenil).; CRP, C-reactive protein; LVEF, left ventricular ejection fraction; NIH, National Institutes of Health; VO2, oxygen consumption. (Source http://ClinicalTrials.gov accessed November 2013.)

cardiovascular event, (a composite of cardiovascular death, non-fatal MI, and stroke). Change from baseline in carotid plaque burden in the bifurcation region of the carotid and changes in the insulin secretion rate (ISR) across the yearly visits will be evaluated. This will allow the detection of new onset type 2 diabetes among patients with pre-diabetes at randomization within the five-year follow-up period (estimated primary completion date: July 2016).

Alternative approaches other than immunomodulation Atherosclerosis immunization It is likely that treatment of atherosclerosis will combine lipid lowering and anti-inflammatory therapies in the future if on-going clinical trials yield positive results. An alternative approach to

Downloaded from cpr.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 22, 2014

XML Template (2014) [2.4.2014–3:52pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CPRJ/Vol00000/140039/APPFile/SG-CPRJ140039.3d

(CPR)

[1–15] [PREPRINTER stage]

Awan and Genest

11

immunomodulation is to teach the very same immune system to self-recognize culprit proteins in the pathogenesis of early inflammation predating atherosclerosis formation.82 Although it may sound theoretically possible, active immunization, passive immunization or acquired tolerance to an antigen by suppression of cellular and humoral immune response to the introduced antigen, are very challenging unlike immunization against a definite pathogen. Interestingly the concept of active immunization against atherosclerosis was surprisingly proposed by Gero et al. more that 50 years ago using beta-lipoprotein,83 yet only in the last 10 years has this proposal received attention in the field. Assisting in this interest is the enhanced understanding of the underlying role of immune responses in atherosclerosis. Furthermore a few laboratories have reported promising results with active immunization using antigenic epitopes within the apoB-100 peptide to reduce atherosclerosis in an apoE-KO mouse.84 These proofof-concept preclinical studies have raised the possibility that such an approach might be possible in humans. Other antigens that have been tested in lab animals to reduce atherosclerosis include; modified LDL, homogenates of plaques, functional group on oxidized phospholipid, heat-shock protein 60 and cholesterol ester transfer protein.84 Regardless of the antigen of choice, counter intuitively, the side effects of lipid antigens or inflammationderived antigens are, so far, cardiovascular in nature.82 As disappointing as this may be, the lifelong protection vaccination against atherosclerosis remains a theoretical goal. The development of such vaccination would have a high impact on the future of atherosclerosis management especially as a primary prevention strategy.

Cyclooxygenase (COX) inhibitors COX-1 and COX-2 inhibitors are largely anti-inflammatory agents that have been associated with small but real adverse cardiovascular effects. However, those effects have really been based on platelet aggregation effects and represent a very different kind of inflammation reduction than that considered in vascular protection.85

Inhibition of phospholipase (PLA) A2 PLAs are a class of enzymes that cleave glycerophospholipids and sphingolipids. At least 19 phospholipase A2 (PLA2) enzymes in man cleave the sn-2 position of phospholipids (glycero- or sphingo-). Lipoprotein-associated PLA2 (Lp-PLA2, also called platelet activating factor acetyl hydrolase), is found mostly on LDL particles (80%) and a small amount on HDL (

Inflammation modulation and cardiovascular disease prevention.

Heart disease and stroke represent the major burden of health worldwide and account for a staggering 17 million deaths yearly. This pandemic is, in gr...
396KB Sizes 0 Downloads 3 Views