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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.
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 [
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 [
]. 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 [
]. 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.) [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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. [
CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.
], 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
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?.
]. 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 [
]. 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 [
Several other processes potentially support a sustained cellular inflammatory response that promotes plaque formation. For example, dyslipidemia and reduced cholesterol efflux [
] 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 [
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 [
], 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 [
]. 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 [
], 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 [
], 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 [
Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease.
] 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 [
]. 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 [
], 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 [
Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset.
]. 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 [
]. 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 [
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 [
]. 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 [
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?.
], 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 [
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 [
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 [
]. 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 [
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.
], and improvement in endothelial function that parallels clinical improvement and reduction in systemic inflammatory markers in patients treated with anti-cytokine therapies [
Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody.
], 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.govNCT02374021) 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 [
]. 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 [
]. 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 [
]. 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) [
]. 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 [
] 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 [
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.
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 [
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 [
]. 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 [
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 [
]. 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 [
Association of circulating levels of neopterin with non-culprit plaque vulnerability in CAD patients an angiogram, optical coherent tomography and intravascular ultrasound 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.[
[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 [
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 [
]. 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 [
]. Importantly improvement or lack thereof in inflammation measured by FDG PET has paralleled clinical outcome responses to drugs such as statins and pioglitazone [
Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
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.
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 [
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 [
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 [
] 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 [
(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.
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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
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.
SOLID-TIMI 52 Investigators Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
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.
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.
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).
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.
SOLID-TIMI 52 Investigators Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
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.
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.
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).
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) [
]. 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 [
]. (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. 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 [
]. 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) [
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 [
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 [
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 [
]. 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 [
]. 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 [
]. 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:
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.
CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.
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?.
Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes.
Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease.
Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset.
Aortic, carotid intima-media thickness and flow- mediated dilation as markers of early atherosclerosis in a cohort of pediatric patients with rheumatic diseases.
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.
Comparative cardiovascular safety of tocilizumab vs etanercept in rheumatoid arthritis: results of a randomized, parallel-group, multicenter, noninferiority, phase 4 clinical trial [abstract].
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.
Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody.
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.
Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy.
Association of circulating levels of neopterin with non-culprit plaque vulnerability in CAD patients an angiogram, optical coherent tomography and intravascular ultrasound study.
[18F]-fluorodeoxyglucose PET/CT imaging as a marker of carotid plaque inflammation: comparison to immunohistology and relationship to acuity of events.
Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features: a comparison between positron emission tomography activity, plaque morphology, and histopathology.
Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
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.
Cells and iron oxide nanoparticles on the move: magnetic resonance imaging of monocyte homing and myocardial inflammation in patients with ST-elevation myocardial infarction.
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.
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.
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.
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).
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.
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.
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