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Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions

      Abstract

      Rudolph Virchow (1821–1902) recognized inflammation in histological preparations of coronary arteries and proposed that inflammation plays a causal role in atherosclerosis. Despite this seminal observation, the main focus of research and drug development programs has been cholesterol alone, and inflammation received less attention over time. However, during the past several decades extensive observations supported the importance of inflammation in the development and destabilization of atherosclerosis. Studies in patients affected by rheumatological diseases suggested an interaction between chronic inflammation and atherosclerotic cardiovascular disease. Randomized clinical studies with lipid lowering agents suggested that part of the beneficial effect may have been related to reduction in inflammation. More recently, a few studies were designed to directly address the role of anti-inflammatory treatments in reducing risk of atherosclerotic heart disease beyond traditional risk factors. In this article, we review the pathophysiologic contribution of inflammation to atherosclerosis, biomarkers of inflammation and the evidence collected in observational studies regarding the role of chronic inflammation in the development of atherosclerotic heart disease. Finally, we discuss the most recent randomized clinical trials of anti-inflammatory agents directed at stemming atherosclerotic cardiovascular disease.

      Keywords

      1. Introduction

      For nearly a century, cholesterol has been considered the primary promoter of atherosclerosis development. First observed in arterial lesions of experimental rabbits in the early 1900s, cholesterol is now unequivocally recognized as a genetic and environmental driver of atherosclerotic disease [
      • Steinberg D.
      Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy.
      ]. Mechanistic understanding of the disease arose first from the ‘response to injury’ hypothesis put forward by Russell Ross, who postulated that endothelial injury induced proliferation and expansion of smooth muscle cells in the intimal space [
      • Ross R.
      • Glomset J.A.
      The pathogenesis of atherosclerosis (first of two parts).
      ]. Although the observation that the atherosclerotic lesion is replete with inflammatory cells was made in the late 1800s, the contribution of immune cells to disease development began to be appreciated only in the last few decades [
      • Libby P.
      Inflammation in atherosclerosis.
      ]. The discovery of the contributions of the innate and adaptive immune system to atherogenesis has led to a refined understanding of lesion development that bridges both the cholesterol and injury hypotheses, and has led to a new line of inquiry for therapeutics to reduce vascular disease burden.

      1.1 Retention and modification of lipoproteins

      The initiating step in the development of atherosclerosis is the accumulation of low-density lipoproteins (LDL) that become sequestered in the subendothelial space by adhering to extracellular matrix proteins rich in proteoglycans (reviewed in Williams et al.) [
      • Williams K.J.
      • Tabas I.
      The response-to-retention hypothesis of early atherogenesis.
      ]. LDL can accumulate as a result of changes in endothelial permeability and paracellular transport between leaky cells or, as more recently described, through active receptor-mediated transcytosis across the cell membrane by transporters like SR-BI and Alk1 [
      • Kraehling J.R.
      • Chidlow J.H.
      • Rajagopal C.
      • et al.
      Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells.
      ,
      • Armstrong S.M.
      • Sugiyama M.G.
      • Fung K.Y.
      • et al.
      A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis.
      ]. These recent studies have provided insight into a mechanism that was previously lacking with regards to how the endothelium enables the accumulation of large particles like LDL. Once in the sub-intimal space, LDL can undergo modification and become aggregated and/or oxidized. The aggregation of LDL results in large complexes ranging in size from 100 nm to 1.0 μm, which can undergo pinocytosis or phagocytosis by immune cells present in the subendothelial space [
      • Kruth H.S.
      Sequestration of aggregated low-density lipoproteins by macrophages.
      ]. The presence of reactive oxygen species and enzymes like lipoxygenases and myeloperoxidases modify both the phospholipid and protein components of LDL particles, rendering them substrates for scavenger receptor mediated uptake. Scavenger receptors present on innate immune phagocytes and antigen-presenting cells have evolved to recognize microbial and ‘non-self’ moieties, which are often in the form of oxidized phospholipids on bacteria [
      • Miller Y.I.
      • Choi S.H.
      • Wiesner P.
      • et al.
      Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity.
      ]. Unlike native LDL uptake through the LDL receptor, scavenger receptor-mediated uptake is not subject to feedback inhibition by intracellular sterol levels, thus phagocytosis and/or receptor mediated uptake can continue unrestricted so long as there exists modified LDL in the extracellular milieu [
      • Getz G.S.
      • Reardon C.A.
      Atherogenic lipids and macrophage subsets.
      ] (Fig. 1).
      Fig. 1
      Fig. 1Schematic and simplified representation of the multiple steps inherent with an atherosclerotic plaque formation and disruption.
      Inf-Y; interferon gamma; MMPs: matrix metalloproteinases; MPO: myeloperoxidase; SMC: smooth muscle cells; Th1: lymphocyte T-helper 1; Th12: lymphocyte T-helper 2; TLR: toll like receptor (reproduced with permission from Raggi P, Alexopoulos N, McLean D, Lerakis S. Assessment of risk in the asymptomatic patient. In: Non-invasive cardiovascular imaging. A multimodality approach. (Editor: Garcia MJ. Lippincott, Williams&Williams, 2011).

      1.2 Recruitment of monocytes and their differentiation into macrophages

      Numerous noxious stimuli (dyslipidemia, smoking, hypertension, abnormal blood rheology, viruses, etc) can cause endothelial damage [
      • Ross R.
      Atherosclerosis–an inflammatory disease.
      ,
      • Tousoulis D.
      • Charakida M.
      • Stefanadis C.
      Endothelial function and inflammation in coronary artery disease.
      ]. The endothelium normally keeps a delicate balance of vasodilation, vasoconstriction and pro- and anti-coagulant activity. In the presence of damaging stimuli the endothelium responds by upregulating the transcriptional messenger NFkB and releasing a series of substances that enhance leukocyte adhesion on the endothelium E-selectin, vascular and inter-cellular adhesion molecules (VCAM-1 and ICAM-1), as well as endothelin and angiotensin II, and pro-coagulant factors. Rolling leukocytes adhere onto the endothelium and penetrate beneath the endothelial layer to reach the subintimal space. Modified lipoproteins are first taken up by tissue-resident dendritic cells and macrophages in the arterial intima [
      • Steinberg D.
      Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.
      ]. Additionally, non-classical ‘patrolling’ monocytes can engulf oxLDL via scavenger receptor CD36 at very early stages of atherogenesis [
      • Marcovecchio P.M.
      • Thomas G.D.
      • Mikulski Z.
      • et al.
      Scavenger receptor CD36 directs nonclassical monocyte patrolling along the endothelium during early atherogenesis.
      ]. Immune cells further induce the expression of endothelial adhesion molecules (e.g. ICAM1) to recruit bone marrow derived monocytes into the intima. As they enter the subendothelial space, monocytes differentiate into macrophages and engulf modified LDL, where excess cholesterol is esterified for storage in lipid droplets, giving macrophages their foam-like appearance. Foam cells induce cytokine and chemokine production and the additional recruitment of circulating immune cells, setting off the sequelae of the inflammatory response. The activation of scavenger receptors, particularly CD36, by modified cholesterol engages innate immune responses downstream of the toll-like receptor pathway [
      • Stewart C.R.
      • Stuart L.M.
      • Wilkinson K.
      • et al.
      CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.
      ]. Most notably, cholesterol crystals induce the activation of the inflammasome in the cytoplasm of the macrophages in the arterial intima. The inflammasome is a protein complex that senses exogenous danger signals and cleaves pro-interleukin-1β (IL-1β) and IL-18 that are then secreted as activated cytokines. [
      • Sheedy F.J.
      • Grebe A.
      • Rayner K.J.
      • et al.
      CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.
      ,
      • Duewell P.
      • Kono H.
      • Rayner K.J.
      • et al.
      NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.
      ], IL-1α is also secreted in response to scavenger receptor activation by modified cholesterol, and has been postulated to play a more potent role in atherogenesis than IL-1β [
      • Freigang S.
      • Ampenberger F.
      • Weiss A.
      • et al.
      Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis.
      ,
      • Sheedy F.J.
      • Moore K.J.
      IL-1 signaling in atherosclerosis: sibling rivalry.
      ]. In the extracellular space, IL-1β, IL-1α and IL-18 interact with their cognate receptors and cause the release of reactive oxygen species, matrix degrading enzymes, activation and proliferation of T-cells and the further production of cytokines [
      • Zheng Y.
      • Gardner S.E.
      • Clarke M.C.
      Cell death, damage-associated molecular patterns, and sterile inflammation in cardiovascular disease.
      ]. Of note, while some T-cells play a pro-atherogenic role such as T-helper-1 (Th1) cells, others have been shown to limit atherosclerosis progression [
      • Libby P.
      • Hansson G.K.
      Taming immune and inflammatory responses to treat atherosclerosis.
      ]. For instance, regulatory T-lymphocytes (TREGs) secrete TGF-beta and IL-10, while T-helper 17 secrete IL-17 and they all help to stem atherosclerosis progression [
      • Gisterå A.
      • Robertson A.K.
      • Andersson J.
      • et al.
      Transforming growth factor-β signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway.
      ]. The signals downstream of IL-1-mediated inflammatory signaling make IL-1β one of the most potent drivers of atherosclerosis, and has thus been a recent focus of therapeutic developments. Of note, one of the major stimuli for IL-1β secretion is IL-1β itself.

      1.3 Vascular smooth muscle cells

      During the formation of a lesion nidus, smooth muscle cells (SMCs) present in the media layer of the artery are exposed to modified cholesterol, cytokines and growth factors, and become activated. They transition from a primarily contractile, non-proliferating phenotype to a proliferating, migratory and matrix-secreting state that populates the arterial intima. Until recently, the contribution of SMCs to lesion formation was thought to be limited to these steps, and SMCs were not believed to contribute directly to the inflammatory events within the plaque. However, SMCs can take up modified lipids and adopt a ‘macrophage-like’ phenotype, expressing macrophage markers on their surface and develop phagocytic activity [
      • Gomez D.
      • Owens G.K.
      Smooth muscle cell phenotypic switching in atherosclerosis.
      ]. Indeed, it is now suggested that up to 50% of the cells in an atherosclerotic plaque that appear to be macrophages may be derived from an SMC lineage [
      • Shankman L.S.
      • Gomez D.
      • Cherepanova O.A.
      • et al.
      KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis.
      ]. Macrophage-like SMCs are not as efficient in phagocytosis nor do they express abundant levels of cholesterol export machinery compared with their immune-derived counterparts, which suggests that therapies targeting these pathways may not be efficient in retarding atherosclerotic plaque development.

      1.4 Cell death and impaired efferocytosis as pro-inflammatory drivers of atherosclerosis

      As the perpetual uptake of LDL into macrophages persists, these cells undergo endothelial reticulum (ER) stress, apoptosis and necroptosis in response to engorgement with lipids [
      • Rayner K.J.
      Cell death in the vessel wall: the good, the Bad, the Ugly.
      ]. This process is due in part to the unfolded protein response (UPR). Cholesterol is toxic to the cell (unless esterified) and triggers the UPR in the ER. ER stress stimulates the production of CCAAT-enhancer-binding protein homologous protein (CHOP) and initiates the release of Ca2+ from the ER, release of cytochrome C from the mitochondria and activation of caspase-dependent apoptosis [
      • Gonzalez L.
      • Trigatti B.L.
      Macrophage apoptosis and necrotic core development in atherosclerosis: a rapidly advancing field with clinical relevance to imaging and therapy.
      ]. Apoptosis in the initial stages of lesion development is protective, reducing lesion cellularity and clearing away cholesterol-engorged cells. This benefit depends however on the efficient removal of apoptotic macrophages from the lesion by efferocytosis, i. e the phagocytosis of dead and dying cells. Efferocytosis in lesions is thought to occur primarily through the cell surface receptor MerTK on macrophages, although other receptors may also play a role. When MerTK activity is impaired, the clearance of dead foam cells is reduced, and apoptotic debris begin to accumulate [
      • Kojima Y.
      • Weissman I.L.
      • Leeper N.J.
      The Role of efferocytosis in atherosclerosis.
      ]. This can also lead to secondary necrosis, wherein an apoptotic cell that is not efficiently cleared undergoes necrotic rupture, but the exact mechanisms by which this occurs are not known. Efferocytosis in advanced lesions might also be compromised due to the relatively limited capacity of SMC-derived foam cells to perform phagocytosis (in comparison to professional phagocytes like macrophages) leading to the accumulation of cell debris within the plaque.
      In addition to apoptosis, necroptosis is another form of programmed cell death that is activated in macrophages after prolonged exposure to oxidized lipoproteins [
      • Karunakaran D.
      • Geoffrion M.
      • Wei L.
      • et al.
      Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.
      ,
      • Leeper N.J.
      The role of necroptosis in atherosclerotic disease.
      ]. Unlike apoptosis, necroptosis incites an inflammatory response by the unregulated release of intracellular contents that serve as activation signals for the innate immune system. It is thought that necroptosis may be active at later stages of lesion development, particularly in humans, where the presence of dead cells with a necrotic morphology dominates over those with apoptotic characteristics. Additionally, components of the necroptotic pathway are found to be active in very advanced, complex lesions in humans, but not in early intimal thickening [
      • Karunakaran D.
      • Geoffrion M.
      • Wei L.
      • et al.
      Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.
      ]. The efferocytosis of necroptotic cells is impaired, which also contributes to the expansion of the necrotic core [
      • Karunakaran D.
      • Geoffrion M.
      • Wei L.
      • et al.
      Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.
      ]. Together, these cell death pathways and the defective clearance of dead cell debris promote lesion necrosis, more inflammation, and ultimately contribute to the instability of the advanced atherosclerotic plaque.

      1.5 Novel pathways: hematopoiesis, inflammation and atherosclerosis

      Ageing is undeniably one of the most powerful determinants of the development of cardiovascular disease. However, what drives development of atherosclerosis with ageing, beyond the obvious prolonged exposure to traditional risk factors, is unclear. Random somatic changes in hematopoietic stem cells may confer a survival advantage to some cell lines with generation of clones of genetically modified cells [
      • Fuster J.J.
      • Walsh K.
      Somatic mutations and clonal hematopoiesis: unexpected potential new drivers of age-related cardiovascular disease.
      ]. This process appears to be a normal developmental occurrence with age in most cell lines, but it is particularly accentuated in the hematopoietic system because of the high cellular proliferation rate. Although these changes may predispose to development of cancer, the majority of patients will host hematopoietic cell clones for prolonged periods of times without developing any malignancy; therefore investigators have termed this condition clonal hematopoiesis of indeterminate potential (CHIP). However, an initial observation highlighted a significant increased risk of all-cause mortality in cancer-free patients who carried CHIP involving approximately 20% of their circulating blood cells [
      • Jaiswal S.
      • Fontanillas P.
      • Flannick J.
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ]. Of interest, the increased mortality was mostly related to a substantial increase in risk of fatal myocardial infarction. A subsequent publication confirmed this observation demonstrating a 2-fold increased risk of myocardial infarction and stroke in carriers of CHIP. Additionally, there was a close association between premature atherosclerotic cardiovascular events and CHIP with a 4-fold increase in risk for patients younger than 50 years [
      • Jaiswal S.
      • Natarajan P.
      • Silver A.J.
      • et al.
      Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.
      ]. Since the association of CHIP with atherosclerosis does not prove causation, some investigators proposed that a low degree of chronic inflammation in patients with risk factors for atherosclerosis may promote somatic changes in hematopoietic cell lines and eventually CHIP [
      • Hasselbalch H.C.
      Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?.
      ,
      • Bonnefond A.
      • Skrobek B.
      • Lobbens S.
      • et al.
      Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications.
      ]. However, a direct link between CHIP and atherosclerosis via pro-active inflammatory pathways has been demonstrated in experimental settings. Although a large number of genes can be affected by somatic mutations and induce CHIP, a few have been detected more often than others. In particular, a mutation in the gene encoding for the enzyme TET2 has been shown in an experimental model to promote clonal hematopoietic expansion and accelerate atherosclerosis in hyperlipidemic mice [
      • Fuster J.J.
      • MacLauchlan S.
      • Zuriaga M.A.
      • et al.
      Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
      ]. Further investigation into the basic mechanisms of acceleration of atherosclerosis in TET2-deficient animals demonstrated an increased secretion of cytokines and chemokines by TET2 deficient macrophages via expression of the NLRP3 inflammasone and IL-1β [
      • Bonnefond A.
      • Skrobek B.
      • Lobbens S.
      • et al.
      Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications.
      ,
      • Cull A.H.
      • Snetsinger B.
      • Buckstein R.
      • Wells R.A.
      • Rauh M.J.
      TET2 restrains inflammatory gene expression in macrophages.
      ].
      Several other processes potentially support a sustained cellular inflammatory response that promotes plaque formation. For example, dyslipidemia and reduced cholesterol efflux [
      • Rahman M.S.
      • Murphy A.J.
      • Woollard K.J.
      Effects of dyslipidaemia on monocyte production and function in cardiovascular disease.
      ,
      • Tall A.R.
      • Yvan-Charvet L.
      • Westerterp M.
      • Murphy A.J.
      Cholesterol efflux: a novel regulator of myelopoiesis and atherogenesis.
      ] as well as dysglycemia [
      • Nagareddy P.R.
      • Murphy A.J.
      • Stirzaker R.A.
      • et al.
      Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.
      ] have been reported to promote monocyte production at the hematopoietic level. Additionally, oxidized LDL promotes the release of epigenetically modified monocytes capable of sustaining a prolonged inflammatory response [
      • Bekkering S.
      • Quintin J.
      • Joosten L.A.B.
      • Meer J.W.M.
      • V D Netea M.G.
      • Riksen N.P.
      Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes.
      ]. Monocytes and macrophages with these phenotypic changes appear to react with sustained responses to noxious stimuli, hence demonstrating an adaptive (i.e long lasting, memory driven) rather than an innate immune response behavior (i.e. a first line defense). Since monocytes have a very limited life span of hours to days, the adaptive response to stimuli (named trained immunity) suggests that epigenetic changes may be occurring at the hematopoietic precursor cell level [
      • Valk F.M.
      • van der Kuijk C.
      • et al.
      Increased haematopoietic activity in patients with atherosclerosis.
      ], although there is no clear evidence of such event at this stage.
      Derailed hematopoiesis may thus represent a very important link between inflammation and atherosclerosis unsuspected until recent times.

      2. Rheumatological diseases and atherosclerosis

      Many rheumatic diseases are characterized by chronically elevated levels of circulating inflammatory cytokines linked to the mechanistic pathways contributing to atherogenesis and atherothrombosis, such as TNF-α, IL-6, IL-1, IL-17 and others [
      • Branen L.
      • Hovgaard L.
      • Nitulescu M.
      • Bengtsson E.
      • Nilsson J.
      • Jovinge S.
      Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein e knockout mice.
      ,
      • Ohta H.
      • Wada H.
      • Niwa T.
      • et al.
      Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in apoe-deficient mice.
      ,
      • Huber S.A.
      • Sakkinen P.
      • Conze D.
      • Hardin N.
      • Tracy R.
      Interleukin-6 exacerbates early atherosclerosis in mice.
      ,
      • Kirii H.
      • Niwa T.
      • Yamada Y.
      • et al.
      Lack of interleukin-1beta decreases the severity of atherosclerosis in apoe-deficient mice.
      ,
      • Charles P.
      • Elliott M.J.
      • Davis D.
      • et al.
      Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis.
      ]. Circulating levels of these cytokines vary between diseases and between individuals with a given rheumatic disease, they tend to fluctuate over time, and are affected by treatment. During the active phase of diseases, the circulating levels of cytokines tend to be orders of magnitude greater than levels implicated in atherogenesis and atherothrombosis in the general population [
      • Duff G.W.
      Cytokines and acute phase proteins in rheumatoid arthritis.
      ,
      • Ridker P.M.
      • Rifai N.
      • Pfeffer M.
      • Sacks F.
      • Lepage S.
      • Braunwald E.
      Elevation of tumor necrosis factor-{alpha} and increased risk of recurrent coronary events after myocardial infarction.
      ,
      • Ridker P.M.
      • Rifai N.
      • Stampfer M.J.
      • Hennekens C.H.
      Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.
      ], thus providing a natural framework in humans to explore putative associations between inflammation and atherosclerosis.
      Among rheumatic diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have been the most widely studied with regard to the link between inflammation and atherosclerosis. More recently, an awareness that elevated CVD risk extends to individuals with psoriasis and psoriatic arthritis has also emerged. Across multiple studies [
      • Avina-Zubieta J.A.
      • Choi H.K.
      • Sadatsafavi M.
      • Etminan M.
      • Esdaile J.M.
      • Lacaille D.
      Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies.
      ,
      • Avina-Zubieta J.A.
      • Thomas J.
      • Sadatsafavi M.
      • Lehman A.J.
      • Lacaille D.
      Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies.
      ,
      • Yurkovich M.
      • Vostretsova K.
      • Chen W.
      • Avina-Zubieta J.A.
      Overall and cause-specific mortality in patients with systemic lupus erythematosus: a meta-analysis of observational studies.
      ], individuals with these disease states have been shown to have on average a higher risk of CVD events and mortality relative to the general population, and events tend to occur at an earlier age [
      • Wolfe F.
      • Mitchell D.M.
      • Sibley J.T.
      • et al.
      The mortality of rheumatoid arthritis.
      ]. For RA, CVD mortality and incident MI are 50% higher compared with matched controls [
      • Tall A.R.
      • Yvan-Charvet L.
      • Westerterp M.
      • Murphy A.J.
      Cholesterol efflux: a novel regulator of myelopoiesis and atherogenesis.
      ,
      • Nagareddy P.R.
      • Murphy A.J.
      • Stirzaker R.A.
      • et al.
      Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.
      ]. For SLE, the aggregate risk of MI is 5- to 10-fold higher compared with the general population [
      • Schoenfeld S.R.
      • Kasturi S.
      • Costenbader K.H.
      The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review.
      ], although it is 52-fold higher for women between the age of 35–44 years [
      • Manzi S.
      • Meilahn E.N.
      • Rairie J.E.
      • et al.
      Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham study.
      ]. Underlying this increased rate of CVD events in both diseases, multiple cross-sectional and cohort studies [
      • Tyrrell P.N.
      • Beyene J.
      • Feldman B.M.
      • McCrindle B.W.
      • Silverman E.D.
      • Bradley T.J.
      Rheumatic disease and carotid intima-media thickness: a systematic review and meta-analysis.
      ,
      • Giles J.T.
      • Szklo M.
      • Post W.
      • et al.
      Coronary arterial calcification in rheumatoid arthritis: comparison to the multi-ethnic study of atherosclerosis.
      ,
      • Chung C.P.
      • Oeser A.
      • Raggi P.
      • et al.
      Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors.
      ,
      • Asanuma Y.
      • Oeser A.
      • Shintani A.K.
      • et al.
      Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
      ,
      • Kao A.H.
      • Krishnaswami S.
      • Cunningham A.
      • et al.
      Subclinical coronary artery calcification and relationship to disease duration in women with rheumatoid arthritis.
      ,
      • Karpouzas G.A.
      • Malpeso J.
      • Choi T.Y.
      • Li D.
      • Munoz S.
      • Budoff M.J.
      Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease.
      ,
      • Rho Y.H.
      • Chung C.P.
      • Oeser A.
      • et al.
      Novel cardiovascular risk factors in premature coronary atherosclerosis associated with systemic lupus erythematosus.
      ] conducted with various atherosclerosis imaging techniques [i.e. carotid ultrasound, cardiac computed tomography (CT) for coronary artery calcium (CAC) and CT angiography] confirmed a greater burden of atherosclerosis relative to population-based controls, even after adjusting for relevant demographic, lifestyle, and CVD risk factors. In one study, RA patients younger than 55 years of age with the most active and severe manifestations of the disease had a CAC score equivalent to that of a 65-year-old individual without RA [
      • Kirii H.
      • Niwa T.
      • Yamada Y.
      • et al.
      Lack of interleukin-1beta decreases the severity of atherosclerosis in apoe-deficient mice.
      ]. In addition to a higher burden of atherosclerosis, the characteristics of coronary atherosclerotic plaques also appear to differ in RA patients. In one histopathologic study [
      • Aubry M.C.
      • Maradit-Kremers H.
      • Reinalda M.S.
      • Crowson C.S.
      • Edwards W.D.
      • Gabriel S.E.
      Differences in atherosclerotic coronary heart disease between subjects with and without rheumatoid arthritis.
      ], coronary arteries from RA patients exhibited more features of plaque vulnerability and a more extensive inflammatory cellular infiltrate compared with matched non-RA control arteries.
      The exact mechanisms underlying the higher burden of coronary atherosclerosis and plaque vulnerability are not clear. The predominant theory implicates chronic and/or high level of systemic inflammation, and several studies of CVD in RA have indeed identified those with the highest inflammatory burden (i.e. area-under-the-curve determinations of serial inflammatory markers) as being those with the highest risk of CVD events [
      • Innala L.
      • Moller B.
      • Ljung L.
      • Magnusson S.
      • et al.
      Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study.
      ,
      • Wallberg-Jonsson S.
      • Johansson H.
      • Ohman M.L.
      • Rantapaa-Dahlqvist S.
      Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset.
      ]. Some investigators also linked inflammatory burden with progression of atherosclerosis on serial imaging [
      • Giles J.T.
      • Post W.S.
      • Blumenthal R.S.
      • et al.
      Longitudinal predictors of progression of carotid atherosclerosis in rheumatoid arthritis.
      ,
      • Pope J.E.
      • Nevskaya T.
      • Barra L.
      • Parraga G.
      Carotid artery atherosclerosis in patients with active rheumatoid arthritis: predictors of plaque occurrence and progression over 24 weeks.
      ]. However, a number of other factors limit the ability of observational studies of rheumatic disease patients to fully validate a causal link between inflammation and atherosclerosis. Among these, quantifying “inflammation” over multiple decades of a chronic disease is almost impossible as is capturing the early pre-treatment phases of disease when inflammation is often at its highest levels. Corticosteroids are frequently used, particularly in patients with the most active and/or treatment resistant disease, and joint pain in the setting of active inflammation is associated with less physical activity and a decline in physical fitness, both of which may confound the assessment of the association between systemic inflammation and atherosclerosis [
      • Davis 3rd, J.M.
      • Maradit Kremers H.
      • Crowson C.S.
      • et al.
      Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study.
      ,
      • del Rincon I.
      • Battafarano D.F.
      • Restrepo J.F.
      • Erikson J.M.
      • Escalante A.
      Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis.
      ,
      • del Rincon I.
      • O'Leary D.H.
      • Haas R.W.
      • Escalante A.
      Effect of glucocorticoids on the arteries in rheumatoid arthritis.
      ]. Finally, autoantibodies and other non-inflammatory autoimmune features of rheumatic diseases, such as antiphospholipid and anti-endothelial antibodies in SLE, may be disease-specific contributors to atherosclerosis and atherothrombosis, making it tenuous to assert that high levels of systemic inflammation in the most studied rheumatic diseases account fully for their elevated CVD risk.
      Two lines of evidence may aid in disentangling these factors. The first are studies of specific pharmacotherapies in RA that point to CVD risk reduction (discussed below). The second are studies of CVD in auto-inflammatory diseases, characterized by very high circulating levels of inflammatory cytokines in the absence of autoantibodies. These diseases are much rarer than RA, SLE, or the psoriatic diseases, and are thus more difficult to study. However, studies of individuals with familial Mediterranean fever (FMF) and juvenile idiopathic arthritis (JIA) preliminarily demonstrated a link with atherogenesis [
      • Yuksel S.
      • Ayvazyan L.
      • Gasparyan A.Y.
      Familial Mediterranean fever as an emerging clinical model of atherogenesis associated with low-grade inflammation.
      ,
      • Del Giudice E.
      • Dilillo A.
      • Tromba L.
      • et al.
      Aortic, carotid intima-media thickness and flow- mediated dilation as markers of early atherosclerosis in a cohort of pediatric patients with rheumatic diseases.
      ]. However, even for these disorders it remains difficult to disentangle the effect of treatment, particularly glucocorticoids, and the effect of other risk factors such as obesity and physical inactivity with which these chronic diseases are often associated [
      • Bohr A.H.
      • Fuhlbrigge R.C.
      • Pedersen F.K.
      • de Ferranti S.D.
      • Muller K.
      Premature subclinical atherosclerosis in children and young adults with juvenile idiopathic arthritis. A review considering preventive measures.
      ]. Thus, although strong circumstantial evidence linking inflammation and CVD has emerged from the study of rheumatic disease patients, it remains to be demonstrated that a true cause and effect exists and that the magnitude of the effect is independent of other non-inflammatory contributors.

      3. Inflammation as a target of therapy

      In studies of atherosclerosis-prone mice, genetic knockout or inhibition of individual inflammatory cytokines (e.g. IL-1 [
      • Hasselbalch H.C.
      Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?.
      ], TNF [
      • Jaiswal S.
      • Fontanillas P.
      • Flannick J.
      • et al.
      Age-related clonal hematopoiesis associated with adverse outcomes.
      ], IL-17 [
      • Fuster J.J.
      • MacLauchlan S.
      • Zuriaga M.A.
      • et al.
      Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
      ], and others) resulted in a markedly lower burden of atherosclerosis. In humans, current evidence primarily derives from observational studies comparing CVD event rates in rheumatic disease patients, primarily RA, treated with specific agents or from pre-vs. post-treatment comparisons of intermediate CVD endpoints.
      Multiple longitudinal cohort studies have shown CVD event reduction among RA patients treated with methotrexate (compared with other non-biologic treatments). From a pooled analysis of 8 studies [
      • Roubille C.
      • Richer V.
      • Starnino T.
      • et al.
      The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.
      ], methotrexate use was associated with a 28% relative reduction in total CVD events and a 19% reduction in myocardial infarction (MI). Across cohort studies of RA patients treated with TNF inhibitors, TNF inhibitor use has been reported to be associated with a 30% relative reduction in total CVD events and a 41% reduction in MI compared with other treatments, typically non-biologics. CVD event rates among RA patients treated with the IL-6 inhibitor tocilizumab were similar to those of a comparison group treated with TNF-inhibitors in an analysis of insurance claims data [
      • Zhang J.
      • Xie F.
      • Yun H.
      • et al.
      Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis.
      ,
      • Kim S.C.
      • Solomon D.H.
      • Rogers J.R.
      • et al.
      Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a multi-database cohort study.
      ] and in a clinical trial assessing CVD events [
      • Giles J.T.
      • Sattar N.
      • Gabriel S.E.
      • et al.
      Comparative cardiovascular safety of tocilizumab vs etanercept in rheumatoid arthritis: results of a randomized, parallel-group, multicenter, noninferiority, phase 4 clinical trial [abstract].
      ]. Whether these observed effects are directly related to the reduction of circulating inflammatory cytokines or indirectly through other off-target effects is unclear. Beyond its ability to reduce macrophage secretion of pro-inflammatory cytokines, another potential atheroprotective effect of methotrexate is an impact on reverse cholesterol transport [
      • Reiss A.B.
      • Carsons S.E.
      • Anwar K.
      • et al.
      Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human thp-1 monocyte/macrophages.
      ]. In fact, in in-vitro experiments methotrexate has been shown to reduce degradation of the reverse cholesterol transport proteins 27-hydroxylase and ATP-binding cassette transporter A1 (ABCA1) via activation of the A2A adenosine receptor [
      • Reiss A.B.
      • Carsons S.E.
      • Anwar K.
      • et al.
      Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human thp-1 monocyte/macrophages.
      ]. In contrast, the ability of TNF inhibitors to impact CVD event rates appears to be reliant on clinical efficacy [
      • Dixon W.G.
      • Watson K.D.
      • Lunt M.
      • Hyrich K.L.
      British Society for Rheumatology Biologics Register Control Centre C; Silman AJ, Symmons DP, British Society for Rheumatology Biologics Register. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British society for rheumatology biologics register.
      ]. Other potential anti-atherogenic effects of immunomodulators include reduction in the expression of vascular adhesion molecules [
      • Gonzalez-Gay M.A.
      • Garcia-Unzueta M.T.
      • De Matias J.M.
      • et al.
      Influence of anti-TNF-alpha infliximab therapy on adhesion molecules associated with atherogenesis in patients with rheumatoid arthritis.
      ], and improvement in endothelial function that parallels clinical improvement and reduction in systemic inflammatory markers in patients treated with anti-cytokine therapies [
      • Gonzalez-Juanatey C.
      • Testa A.
      • Garcia-Castelo A.
      • Garcia-Porrua C.
      • Llorca J.
      • Gonzalez-Gay M.A.
      Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody.
      ,
      • Hurlimann D.
      • Forster A.
      • Noll G.
      • et al.
      Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.
      ]. Evidence that TNF inhibitor use is associated with a lower rate of atherosclerosis progression over time is limited to observational studies [
      • Schoenfeld S.R.
      • Kasturi S.
      • Costenbader K.H.
      The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review.
      ]. In a small uncontrolled study [
      • Maki-Petaja K.M.
      • Elkhawad M.
      • Cheriyan J.
      • et al.
      Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.
      ], TNF-inhibitor use in 17 R A patients was associated with a marked reduction in aortic wall inflammation imaged with FDG-PET CT. Ultimately, these studies provided only circumstantial evidence for the ability of immunomodulators to reduce CVD events. The ideal trial of an immunomodulator compared against placebo with CVD events as the primary outcome would be unethical, as the placebo group would have to suffer with active RA for the length of time required to observe CVD events or follow the progression of atherosclerosis on sequential imaging studies. An ongoing randomized trial is exploring the effects of biologic vs. non-biologic immunotherapies on vascular inflammation assessed with FDG-PET in individuals with RA. This trial, the Treatments Against RA and Effect on FDG PET-CT (TARGET) trial (clinicaltrials.gov NCT02374021) will provide direct evidence of the impact of reduction of systemic inflammation on vascular inflammation and an opportunity to gain insight into potential atheroprotective mechanisms that may be applicable to the general population.

      4. Biomarkers

      A variety of inflammatory biomarkers have been studied representing different inflammatory pathways implicated in the initiation and progression of atherosclerosis.

      4.1 Circulating biomarkers

      Of the various inflammatory biomarkers reported to date, C-reactive protein (CRP) is the most extensively studied [
      • Ridker P.M.
      A test in context: high-sensitivity c-reactive protein.
      ]. As the levels of CRP produced in response to vascular inflammation are quite small, high-sensitivity CRP (hs-CRP) assay methods have been used to estimate small changes in CRP concentrations. In a large metanalysis of >150,000 subjects each standard deviation increase in log-normalized hsCRP was associated with a multivariate adjusted relative increase in risk of 1.37 for future CAD (95% confidence interval 1.27–1.48) and 1.55 (95% CI interval 1.37–1.76) for future cardiovascular (CV) mortality [
      • Kaptoge S.
      • Di Angelantonio E.
      • Lowe G.
      • et al.
      C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant metaanalysis.
      ]. Levels of hsCRP<1, 1–3, and >3 mg/L in this metanalysis were associated with lower, average, and higher relative risk respectively in the context of other traditional risk factors [
      • Bohr A.H.
      • Fuhlbrigge R.C.
      • Pedersen F.K.
      • de Ferranti S.D.
      • Muller K.
      Premature subclinical atherosclerosis in children and young adults with juvenile idiopathic arthritis. A review considering preventive measures.
      ]. In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, the investigators showed that rosuvastatin reduced the rate of first myocardial infarction, stroke, or confirmed CV death by 47% in patients with low-density lipoprotein-C levels of <130 mg/dl and hsCRP of >2 mg/L (hazard ratio: 0.53; 95% confidence interval: 0.40 to 0.69; p < 0.00001) [
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.
      • et al.
      JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      ]. However, since the investigators did not enroll patients with a baseline hsCRP < 2 mg/L there is no evidence to suggest that rosuvastatin may not have been effective even in patients with a low level of this inflammatory marker. Finally, hsCRP has been shown to be associated with the risks of plaque rupture and vascular thrombosis [
      • Burke A.P.
      • Tracy R.P.
      • Kolodgie F.
      • et al.
      Elevated C reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies.
      ] but its prognostic value for future CV events in patients who are on optimal preventive medications (including anti-platelet agents and statins) is weak in secondary prevention studies [
      • Riedel M.
      • Lafitte M.
      • Pucheu Y.
      • Latry K.
      • Couffinhal T.
      Prognostic value of high-sensitivity C-reactive protein in a population of post-acute coronary syndrome patients receiving optimal medical treatment.
      ]. Despite its utility as a marker of risk, Mendelian randomization studies disproved a causal link between CRP and atherosclerosis [
      • Lawlor D.A.
      • Harbord R.M.
      • Timpson N.J.
      • et al.
      The association of C-reactive protein and CRP genotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants.
      ,
      • Hage F.G.
      • Szalai A.J.
      The role of C-reactive protein polymorphisms in inflammation and cardiovascular risk.
      ], in contrast with a strong evidence for IL-6 [
      • Holmes M.V.
      • Kuchenbaecker K.B.
      • et al.
      Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Swerdlow DI
      The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
      ]. Accordingly, Interluekin (IL)-6 signaling has been related to plaque destabilization, to microvascular dysfunction and to adverse outcomes in the setting of acute ischemia [
      • Schieffer B.
      • Selle T.
      • Hilker A.
      • et al.
      Impact of interleukin-6 on plaque development and morphol- ogy in experimental atherosclerosis.
      ,
      • Lindmark E.
      • Diderholm E.
      • Wallentin L.
      • Siegbahn A.
      Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy.
      ]. As IL-1β, the primary circulating form of IL-1 (the most powerful inducers of innate immunity) cannot be reliably measured in plasma, there are no comparable epidemiologic studies relating IL-1β to CV risk [
      • Dinarello C.A.
      Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
      ]. Other chemokines such as IL-8, interferon-inducible protein of 10 kD, and monocyte chemoattractant protein 1 have also been reported to play a significant role in the development of atherosclerosis [
      • Weber C.
      • Schober A.
      • Zernecke A.
      Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease.
      ].
      Monocytes play a primary role in atherogenesis and in plaque progression towards vulnerability. The assessment and characterization of circulating monocytes is useful in detecting plaque vulnerability [
      • Gordon S.
      • Taylor P.R.
      Monocyte and macrophage heterogeneity.
      ]. A functionally distinct subset of CD14+ cells with variable degrees of inflammatory activity (intermediate CD14++CD16+ monocytes) has been identified which is more active in terms of pro-inflammatory cytokine and infiltration of the arterial wall than the classical CD14++CD16 subset. Patients with CV risk factors but without prior clinical cardiovascular events display an expansion of CD16+ monocytes compared with healthy subjects [
      • Rogacev K.S.
      • Ulrich C.
      • Blömer L.
      • et al.
      Monocyte heterogeneity in obesity and subclinical atherosclerosis.
      ].
      Other novel inflammatory biomarkers which are less well studied but of potential value include neopterin [
      • Sun Y.
      • He J.
      • Tian J.
      • Xie Z.
      • Wang C.
      • Yu B.
      Association of circulating levels of neopterin with non-culprit plaque vulnerability in CAD patients an angiogram, optical coherent tomography and intravascular ultrasound study.
      ] and pregnancy-associated plasma protein-A [
      • Wu X.F.
      • Yang M.
      • Qu A.J.
      • et al.
      Level of pregnancy-associated plasma protein-a correlates with coronary thin-cap fibroatheroma burden in patients with coronary artery disease: novel findings from 3-vessel virtual histology intravascular ultrasound assessment.
      ] associated with vulnerable plaque features such as thin-cap fibroatheroma in CAD patients; growth differentiation factor-15, [
      • Wollert K.C.
      • Kempf T.
      • Peter T.
      • Olofsson S.
      • James S.
      • Johnston N.
      • et al.
      Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome.
      ] galectin-3 binding protein [
      • Gleissner C.A.
      • Erbel C.
      • Linden F.
      • et al.
      Galectin-3 binding protein, coronary artery disease and cardiovascular mortality: insights from the LURIC study.
      ] and fibrinogen [
      • Kaptoge S.
      • Di Angelantonio E.
      • Pennells L.
      • et al.
      C-reactive protein, fibrinogen, and cardiovascular disease prediction.
      ] with prognostic potential; and pentraxin 3 [
      • Leary P.J.
      • Jenny N.S.
      • Barr R.G.
      • et al.
      Pentraxin-3 and the right ventricle: the Multi-Ethnic Study of Atherosclerosis-right ventricle study.
      ] and Soluble ST2 [
      • Andersson C.
      • Enserro D.
      • Sullivan L.
      • et al.
      Relations of circulating GDF-15, soluble ST2, and troponin-I concentrations with vascular function in the community: the Framingham Heart Study.
      ] associated with risk factors for atherosclerosis respectively.

      4.2 Imaging biomarkers

      Positron emission tomography (PET) is increasingly being used for the assessment of arterial inflammation and to test the efficacy of therapeutic interventions aimed at reducing inflammation and thus atherosclerosis progression.[
      • Joseph P.
      • Tawakol A.
      Imaging atherosclerosis with positron emission tomography.
      ,
      • Cocker M.S.
      • Spence J.D.
      • Hammond R.
      • et al.
      [18F]-fluorodeoxyglucose PET/CT imaging as a marker of carotid plaque inflammation: comparison to immunohistology and relationship to acuity of events.
      ] 18F-fluorodeoxyglucose (FDG) (Fig. 2), which detects plaque macrophages and other proliferating cells within atherosclerotic plaques in large arteries, is the most widely validated and utilized PET tracer to assess arterial inflammation. FDG uptake is increased in carotid plaques of patients with recent symptoms [
      • Rudd J.H.
      • Warburton E.A.
      • Fryer T.D.
      • et al.
      Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography.
      ]. It has been validated against macrophage staining and gene expression for CD68 and recently leukocyte staining for CD45 [
      • Tawakol A.
      • Migrino R.Q.
      • Bashian G.G.
      • et al.
      In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients.
      ,
      • Graebe M.
      • Pedersen S.F.
      • Højgaard L.
      • Kjaer A.
      • Sillesen H.
      18FDG PET and ultrasound echolucency in carotid artery plaques.
      ,
      • Figueroa A.L.
      • Subramanian S.S.
      • Cury R.C.
      • et al.
      Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features: a comparison between positron emission tomography activity, plaque morphology, and histopathology.
      ]. In a study of 513 cancer patients with no known cardiovascular disease, increased aorta FDG uptake predicted cardiovascular events over a 4.2 year follow-up period [
      • Figueroa A.L.
      • Abdelbaky A.
      • Truong Q.A.
      • et al.
      Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events.
      ]. In one of few prospective outcome studies evaluating a PET tracer, in 60 patients with recent cerebrovascular events, greater FDG uptake predicted increased risk of recurrent events [
      • Marnane M.
      • Merwick A.
      • Sheehan O.C.
      • et al.
      Carotid plaque inflammation on 18 F-fluorodeoxyglucose positron emission tomography predicts early stroke recurrence.
      ]. Importantly improvement or lack thereof in inflammation measured by FDG PET has paralleled clinical outcome responses to drugs such as statins and pioglitazone [
      • Tawakol A.
      • Fayad Z.A.
      • Mogg R.
      • et al.
      Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
      ,
      • Mizoguchi M.
      • Tahara N.
      • Tahara A.
      • et al.
      Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta.
      ].
      Fig. 2
      Fig. 2Axial image of the chest; magnetic resonance image (MRI) on the left and PET FDG image on the right.
      The MRI image shows a normal anatomical structure of the ascending and descending aorta, while the PET image shows FDG uptake both in the ascending (left upper arrow pointing down) and descending (right bottom arrow pointing down) aorta, suggesting the presence of inflammatory infiltrates in the vessel wall.
      Limitations of FDG PET as with other PET tracers for inflammation include: a) small and single centre studies; b) limited prospective data; c) there are no data using FDG to direct treatment; d) anatomical resolution of FDG scans is low; e) there is no consensus on analysis approach (standard uptake value (SUV) versus tissue to blood ratio (TBR) nor the cutpoints to predict outcome; f) radiation exposure. These are also challenges specific to coronary artery imaging including: background myocardial contamination, cardiorespiratory motion, and partial-volume effects due to the relatively small coronary artery vessel size. All of these factors reduce the reliability of PET imaging for coronary arteries especially in the mid to distal segments.
      Novel PET tracers have been investigated to overcome FDG limitations for coronary imaging. These include: 68Ga-DOTATATE that links to the up-regulated somatostatin receptor 2 in macrophages and damaged endothelial cells; 11C-PK11195, which targets activated macrophages translocator protein receptors; 18F-FMCH that targets macrophage cell membranes; 68Ga-NOTA-RGD and 18F-Galacto-RGD that target integrin αvβ3 expression on activated endothelial cells are actively being investigated in both the preclinical and the clinical research arena [
      • Tarkin J.M.
      • Joshi F.R.
      • Evans N.R.
      • et al.
      Detection of atherosclerotic inflammation by (68)Ga-DOTATATE PET compared to [(18)F]FDG PET imaging.
      ,
      • Gaemperli O.
      • Shalhoub J.
      • Owen D.R.
      • et al.
      Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography.
      ,
      • Paeng J.C.
      • Lee Y.S.
      • Lee J.S.
      • et al.
      Feasibility and kinetic characteristics of (68)Ga-NOTA-RGD PET for in vivo atherosclerosis imaging.
      ].
      Several other novel techniques can be used for molecular imaging of arterial inflammation. These include surface ultrasound using targeted microbubbles against vascular cell adhesion molecules [
      • Khanicheh E.
      • Qi Y.
      • Xie A.
      • et al.
      Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties.
      ], and magnetic resonance imaging with ultrasmall superparamagnetic iron oxide [
      • Sosnovik D.E.
      • Nahrendorf M.
      Cells and iron oxide nanoparticles on the move: magnetic resonance imaging of monocyte homing and myocardial inflammation in patients with ST-elevation myocardial infarction.
      ] to detect macrophage content in atherosclerotic plaque. 3-D ultrasound and 18F-sodium fluoride PET (Fig. 3) have been shown to identify vulnerable plaques in carotid [
      • Kuk M.
      • Wannarong T.
      • Beletsky V.
      • Parraga G.
      • Fenster A.
      • Spence J.D.
      Volume of carotid artery ulceration as a predictor of cardiovascular events.
      ] and coronary arteries [
      • Joshi N.V.
      • Vesey A.T.
      • Williams M.C.
      • et al.
      18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial.
      ] respectively. While the latter two tests do not directly image plaque inflammation they identify features of plaque vulnerability which have been correlated to inflammatory burden. Ongoing network studies such as the Canadian Atherosclerosis Imaging Network (CAIN) will shed more light on the application of imaging to evaluate plaque to predict disease progression and clinical outcomes [
      • Tardif J.C.
      • Spence J.D.
      • Heinonen T.M.
      • et al.
      Atherosclerosis imaging and the Canadian atherosclerosis imaging network.
      ].
      Fig. 3
      Fig. 3Example of PET-CT study with sodium 18F-fluoride.
      (A) Coronal (left), sagittal (middle) and axial (right) computer tomography (CT) views of the neck and head of a patient who suffered a recent amaurosis fugax. The crosshairs point at an area of calcification along the right carotid artery. (B) Fusion of PET images obtained with sodium 18F-fluoride and CT images. The area of calcification seen on CT shows increased radiotracer uptake, suggestive of active hydroxyapatite deposition in the atherosclerotic lesion.

      5. Clinical trials of anti-inflammatory agents

      The demonstration that pharmacological modulation of inflammation can reduce cardiovascular events has been challenging. While many agents can modulate the inflammatory response, off-target effects may offset the potential beneficial effects. A good example is the use of glucocorticoids. In a meta-analysis of the effects of glucocorticoids used in over 100,000 patients with chronic inflammatory diseases and controls, the authors reported an increase risk of atherosclerotic cardiovascular events among treated patients irrespective of the timing, dose or cumulative dose of corticosteroids [
      • Souverein P.C.
      • Berard A.
      • Van Staa T.P.
      • et al.
      Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study.
      ]. This may have been due in part to the effects of glucocorticoids on cardiovascular risk factors such as plasma lipids and lipoprotein lipid levels, blood pressure, weight gain and insulin resistance.
      The selective inhibitors of cyclo-oxygenase (COX2) are very effective in reducing arthritic pains. However, the signal of cardiovascular harm reported with the COX2 inhibitor rofecoxib prompted a lengthy re-evaluation of this therapeutic class. A statistically non-significant signal of harm with ibuprofen and diclofenac was reported when compared with naproxen [
      • Patrono C.
      • Baigent C.
      Nonsteroidal anti-inflammatory drugs and the heart.
      ]. In an attempt to provide clinicians with guidance on the use of non-steroidal anti-inflammatory drugs, the large PRECISION Study compared celocoxib, with ibuprofen and naproxen in over 27,000 subjects with arthritis and did not identify a signal of increased cardiovascular disease with celocoxib over ibuprofen and naproxen [
      • Nissen S.E.
      • Yeomans N.D.
      • Solomon D.H.
      • et al.
      PRECISION Trial Investigators. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.
      ]. In a recent subanalysis of the same trial focused on patients at high-cardiovascular risk followed for development of major cardiovascular events, gastric and renal events as well as non-cardiac death, celocoxib was safer than ibuprofen and naproxen when administered without aspirin [
      • Reed G.W.
      • Abdallah M.S.
      • Shao M.
      • et al.
      Effect of aspirin coadministration on the safety of celecoxib, naproxen, or ibuprofen.
      ]. The addition of aspirin attenuated the advantage of celocoxib over ibuprofen and naproxen, although celocoxib was still overall safer.
      A large number of inflammatory mediators are produced in response to injury, danger signals, foreign organisms or substances that trigger local and systemic reactions. Multiple pathways have been identified as potential targets for the prevention and treatment of cardiovascular diseases. Table 1 summarizes several trials of agents that modulate a specific pathway, often downstream from the initial insult. Most clinical trials targeting specific downstream targets, such as oxidation of LDL [
      • Tardif J.C.
      • McMurray J.J.
      • Klug E.
      • et al.
      Aggressive reduction of inflammation stops events (ARISE) trial investigators. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial.
      ], secretory and lipoprotein-associated phospholipase A2 (sPLA2 and LpPLA2) [
      • Nicholls S.J.
      • Kastelein J.J.
      • Schwartz G.G.
      • et al.
      VISTA-16 Investigators. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial.
      ,
      • White H.D.
      • Held C.
      • Stewart R.
      • et al.
      STABILITY Investigators
      Darapladib for preventing ischemic events in stable coronary heart disease.
      ,
      • O'Donoghue M.L.
      • Braunwald E.
      • White H.D.
      • et al.
      SOLID-TIMI 52 Investigators
      Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
      ], P-selectin [
      • Tardif J.C.
      • Tanguay J.F.
      • Wright S.R.
      • et al.
      Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial.
      ,
      • Stähli B.E.
      • Gebhard C.
      • Duchatelle V.
      • et al.
      Effects of the P-Selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention according to timing of infusion: insights from the SELECT-ACS trial.
      ] and even the IL-1β inhibitor anakinra [
      • Abbate A.
      • Kontos M.C.
      • Abouzaki N.A.
      • et al.
      Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies).
      ] failed to meet their primary end-points with respect to a decrease in cardiovascular disease or selected surrogate end-point.
      Table 1Clinical trials of inflammation modulation in atherosclerotic cardiovascular disease.
      Pathway/targetAgentTrialn (pts)OutcomeRef.
      Oxidized LDLSuccinobulolARISE6144No benefit[
      • Tardif J.C.
      • McMurray J.J.
      • Klug E.
      • et al.
      Aggressive reduction of inflammation stops events (ARISE) trial investigators. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial.
      ]
      sPLA2VerespladibVISTA-165000No benefit[
      • Nicholls S.J.
      • Kastelein J.J.
      • Schwartz G.G.
      • et al.
      VISTA-16 Investigators. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial.
      ]
      LpPLA2DarapladibSTABILITY15,000No benefit[
      • White H.D.
      • Held C.
      • Stewart R.
      • et al.
      STABILITY Investigators
      Darapladib for preventing ischemic events in stable coronary heart disease.
      ]
      LpPLA2DarapladibSOLID-TIMI 5213,000No benefit[
      • O'Donoghue M.L.
      • Braunwald E.
      • White H.D.
      • et al.
      SOLID-TIMI 52 Investigators
      Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
      ]
      P-selectinInclacumabSELECT-ACS544No benefit[
      • Tardif J.C.
      • Tanguay J.F.
      • Wright S.R.
      • et al.
      Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial.
      ]
      P-selectinInclacumabSELECT-CABG380No benefit[
      • Stähli B.E.
      • Gebhard C.
      • Duchatelle V.
      • et al.
      Effects of the P-Selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention according to timing of infusion: insights from the SELECT-ACS trial.
      ]
      IL-1RIAnakinraIL-HEART182No benefit[
      • Abbate A.
      • Kontos M.C.
      • Abouzaki N.A.
      • et al.
      Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies).
      ]
      Neutrophil mobilityColchicineLoDoCo532Positive[
      • Nidorf S.M.
      • Eikelboom J.W.
      • Budgeon C.A.
      • Thompson P.L.
      Low-dose colchicine for secondary prevention of cardiovascular disease.
      ]
      IL-1βCanakinumabCANTOS10,061Positive[
      • Nidorf S.M.
      • Eikelboom J.W.
      • Budgeon C.A.
      • Thompson P.L.
      Low-dose colchicine for secondary prevention of cardiovascular disease.
      ]
      TNFEtanerceptENTRACTE3080Enrolling
      IL-6TocilizumabENTRACTE3080Enrolling
      Neutrophil mobilityColchicineColCot4500Enrolling
      IL-6, TNFMethotrexateCIRT7000Halted and pending report
      LDL: low-density lipoprotein; sPLA2: secretory phospholipase A2; LpPLA2: lipoprotein-associated phospholipase A2; TNF: tumor necrosis factor; IL: interleukin.
      Colchicine, derived from the plant Colchicum autumnale (“meadow saffron”), is used to treat acute gout attacks and pericarditis. Colchicine inhibits neutrophil motility and activity and has a marked anti-inflammatory effect. Low dose colchicine (0.5 mg/day) was tested in a prospective randomized trial of 532 patients with stable CAD treated according to conventional guidelines (LoDoCo trial) [
      • Nidorf S.M.
      • Eikelboom J.W.
      • Budgeon C.A.
      • Thompson P.L.
      Low-dose colchicine for secondary prevention of cardiovascular disease.
      ]. The primary outcome of acute coronary syndrome, out-of-hospital cardiac arrest, or non cardio-embolic ischemic stroke occurred in 15/282 patients on colchicine and 40/250 patients to placebo (HR: 0.33; 95% CI, 0.18 to 0.59; p < 0.001). The authors concluded that colchicine may be effective to reduce recurrent cardiovascular events in patients with stable atherosclerotic cardiovascular disease (ASCVD). Following the encouraging results of the LoDoCo trial, a larger outcome trial, the Colchicine Cardiovascular Outcomes Trial (COLCOT) was designed to examine the effects of low dose colchicine on cardiovascular events in 4500 patients with an acute coronary syndrome. In this trial, patients are randomized within 30 days of an acute coronary syndrome and after planned percutaneous revascularization to standard of care and colchicine 0.5 mg/day or placebo. Results are expected in 2019 (Clinical trials.gov # NCT02551094, last accessed May 18, 2018).
      Targeting inflammation upstream has become the focus of intense research. New targets of therapy include Interleukin 6 (IL-6), Tumor Necrosis Factor-alpha (TNFα); Interleukin-1β [
      • Ridker P.M.
      From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection.
      ]. (Fig. 4). Several anti-inflammatory treatments have been found to be associated with reduction in cardiovascular events in patients with rheumatic diseases, as discussed in a prior section. Both TNFα and IL-6 monoclonal antibodies are used extensively for the treatment of rheumatoid arthritis, psoriatic arthritis and several chronic inflammatory conditions. A potential limitation of TNFα blockade with etanercept and IL-6 blockade with tocilizumab is the effect on increasing the pro-atherogenic apolipoprotein B containing lipoproteins in plasma. However, the clinical significance of these induced lipoproteins alterations is not yet clear. One large randomized trial just reached its conclusion and another one is still ongoing.
      Fig. 4
      Fig. 4Schematic representation of the contribution of interleukin 1 beta to the inflammatory cascade and potential benefits of its blockade (reproduced with permission from Libby P. J Am Coll Cardiol 2017;70:2278-89).
      In the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial, the Interleukin IL-1β monoclonal antibody canakinumab was administered to 10,061 stable post-myocardial infarction patients with and a high-sensitivity C-reactive protein (hsCRP) > 2 mg/L after at least six weeks for the index event [
      • Ridker P.M.
      • Everett B.M.
      • Thuren T.
      • et al.
      CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease.
      ]. The patients were randomized to receive one of 3 canakinumab doses (50 mg, 150 mg, and 300 mg) administered subcutaneously every 3 months or placebo. All patients received standard of care therapy and the serum LDL level at enrollment had to be within guidelines dictated limits. The primary efficacy end-point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death was met for the 150 mg (HR 0.85; 95% CI, 0.74 to 0.98; p = 0.021) dose. The secondary end-point included a combination of cardiovascular death, non-fatal myocardial infarction and stroke plus hospitalization for unstable angina leading to urgent revascularization and was again reduced with the 150 dose (HR 0.83; 95% CI, 0.73 to 0.95; p = 0.005). Notably, however, cardiovascular mortality was not reduced with any dose of the experimental drug. On the other hand, canakinumab was associated with a higher incidence of fatal infections than placebo (0.31 events ×100 person years for all combined doses vs. 0.18 events ×100 person years for placebo; p = 0.02). The all-cause and cardiovascular mortality was not different among all canakinumab doses. The investigators also pre-specified two exploratory analyses. In the first one, cancer mortality was significantly reduced in the canakinumab group (p = 0.0007) and lung cancer was less frequent in the 150 and 300 mg doses (p = 0.001) [
      • Ridker P.M.
      • MacFadyen J.G.
      • Thuren T.
      • Everett B.M.
      • Libby P.
      • Glynn R.J.
      CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.
      ]. In a second subanalysis, the investigators sought to determine which patients benefited the most from treatment with canakinumab, and specifically focused on the extent of hsCRP reduction in response to treatment [
      • Ridker P.M.
      • MacFadyen J.G.
      • Everett B.M.
      • Libby P.
      • Thuren T.
      • Glynn R.J.
      CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.
      ]. Compared to placebo, MACE was significantly reduced in patients with an hsCRP level <2 mg/L after 3 months of treatment (HR: 0.75 (95%CI 0.663–0.85; p<0.0001) but not in those with an hsCRP >2 mg/L. Among patients who reached a level of hsCRP<2 mg/L there was also a significant 31% reduction in cardiovascular and all-cause mortality (p = 0.0004 and p<0.0001, respectively).
      The investigators calculated a number needed to treat (NNT) of 24 to avoid one myocardial infarction, stroke, coronary revascularization, or death from any cause in the overall CANTOS cohort. However, among patients who reached hsCRP <2 mg/L with canakinumab, the 5 year NNT estimate dropped to 16. In contrast, the estimate increased to 57 for patients who achieved an on-treatment hsCRP >2 mg/L [
      • Ridker P.M.
      • MacFadyen J.G.
      • Everett B.M.
      • Libby P.
      • Thuren T.
      • Glynn R.J.
      CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.
      ].
      Two more subanalyses of the CANTOS trial were recently published. In the first one, no dose of canakinumab was associated with an increase in new onset diabetes mellitus or worsening of hemoglobin A1c levels [
      • Everett B.M.
      • Donath M.Y.
      • Pradhan A.D.
      • et al.
      Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes.
      ]. In the second the authors compared 1872 patients with chronic kidney disease (CKD: estimated glomerular filtration rate <60 ml/min/1.73 m2) with the remaining ∼8000 patients enrolled in CANTOS [
      • Ridker P.M.
      • MacFadyen J.G.
      • Glynn R.J.
      • et al.
      Inhibition of interleukin 1ß and cardiovascular outcomes in patients with chronic kidney disease.
      ]. Canakinumab reduced MACE in CKD patients and was particularly effective in those who achieved a level of hsCRP<2 mg/L after the first drug dose. In patients with hsCRP <2 mg/L MACE, cardiovascular and all-cause mortality were all reduced.
      An ongoing trial, The Cardiovascular Inflammation Reduction Trial (CIRT), designed to evaluate the effects of low dose methotrexate (15–20 mg per week) compared to placebo on myocardial infarction, stroke, and cardiovascular death in patients with chronic ASCVD was just halted by the steering committee. No results have been released yet and there is no indication of either benefit or harm to this date. Patients with type 2 diabetes or metabolic syndrome were preferentially enrolled in this trial because of the probability of a high burden of residual inflammatory risk. The trial results are expected to be reported in the Fall of 2018 (Clinical trials.gov # NCT01594333, last accessed June 2, 2018).

      6. Conclusions

      The contribution of inflammation to the pathophysiology of atherosclerosis is complex and probably not fully understood yet, although numerous advancements have opened the door to new therapeutic avenues. The combination of decades of research into the fundamental biology of inflammation in experimental atherosclerosis, the epidemiological associations between inflammatory biomarkers and the risk of CV disease, and the Mendelian randomization studies showing a causal link between inflammation (IL-6 especially) and CV disease, support the inflammatory hypothesis of atherosclerosis and make it an attractive target of therapy. The recent CANTOS trial results, that modulation of inflammation without altering conventional risk factors decreases the risk of cardiovascular events, provide exciting yet preliminary evidence that approaches to reduce inflammation may become a viable new therapeutic venue. Yet, there remain several dilemmas to be addressed. Therapy with canakinumab was not free of severe and life-threatening complications, although the frequency of some malignancies was reduced. Other drugs on the horizon may carry a similar risk. The cost of biologics is high and, in some cases, prohibitive. What will be the best way to chose patients that may benefit the most from these therapies? The investigators of CANTOS proposed that a simple measurement of a non-specific biomarker such as hsCRP may be sufficient, but these conclusions may not hold for the individual patient while they may be true for a cohort of patients. Potentially molecular imaging will provide a guide for patient and therapeutic agent selection based on the presence of vascular inflammation [
      • Derlin T.
      • Bengel F.M.
      Canakinumab for atherosclerotic disease.
      ]. If all or some of the ongoing trials give positive results, clinicians may become more comfortable in targeting inflammation as another fundamental component of the atherosclerotic process. Although the innate immune system has evolved to serve and protect its host, its aberrant and chronic stimulation can also have detrimental consequences. A more advanced understanding of the inflammatory activation pathways in the vessel wall may lead to designing unique therapies that do not compromise host defense against pathogens. As our understanding of the contribution of inflammation in controlling the development of atherosclerosis expands, we will be able to leverage newly acquired knowledge to develop novel therapies for atherosclerotic heart disease.

      Conflicts of interest

      P. Raggi is a member of the advisory board of Amgen, Sanofi, Novo Nordisk and Novartis.
      J. Genest is a consultant and received honoraria and grants from Sanofi, Amgen, Akcea, Pfizer.
      JT Giles is a consultant for Genentech, Lilly, and Horizon pharmaceuticals. His consultancy for Genentech involves tocilizumab and amounts to <$1000 per year.
      G. Dwivedi received honoraria from Astra Zeneca and Amgen for work unrelated to this publication.
      R. Beanlands is a consultant for: Lantheus Medical Imaging, Jubilant DraxImage, GE, and he receives research funding from: Lantheus Medical Imaging, Jubilant DraxImage, GE. None of these relate directly to this work.
      M. Gupta received honoraria from Amgen, Novartis, Novo Nordisk, and Sanofi. He also received grants from Amgen and Sanofi.

      Financial support

      R Beanlands is a Career Investigator supported by the Heart and Stroke Foundation of Ontario (HSFO) and Tier 1 Research Chair supported by the University of Ottawa , and University of Ottawa Heart Institute Vered Chair in Cardiology . JT Giles is supported by unrestricted research funding from Pfizer not associated with this publication. G. Dwivedi is the Wesfarmers Chair in Cardiology at the Harry Perkins Institute of Medical Research, WA, Australia .

      Appendix A. Supplementary data

      The following are the supplementary data related to this article:

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