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Immune dysregulation and inflammation contributes to atherosclerotic plaque.
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Increased inflammatory biomarkers are correlated with a higher cardiovascular risk.
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Therapy impacts outcomes, affirming the inflammatory hypothesis of atherosclerosis.
Abstract
Cardiovascular disease remains the leading cause of death worldwide with coronary atherosclerotic heart disease being the largest contributor. The mechanisms behind the presence and progression of atherosclerosis remain an area of intense scientific focus. Immune dysregulation and inflammation are key contributors to the development of an atherosclerotic plaque and its progression to acute coronary syndromes. Increased circulating levels of biomarkers of systemic inflammation including hsCRP are correlated with a higher cardiovascular risk. Targeting specific inflammatory pathways implicated in atherosclerotic plaque formation is an exciting area of ongoing research. Target specific therapies directed at pro-inflammatory cytokines such as IL-1β, IL-6, TNFα, and CCL2 have demonstrated slowing in the progression of atherosclerosis in animal models and improved cardiovascular outcomes in human subjects. Most notably, treatment with the monoclonal antibody canakinumab, which directly targets and neutralizes IL-1β, was recently shown to be associated with reduced risk of adverse cardiovascular events compared to placebo in a randomized, placebo-controlled trial. Several other therapies including colchicine, methotrexate and leukotriene inhibitors demonstrate the potential for lowering cardiovascular risk through immunomodulation, though further studies are needed. Understanding the role of inflammation in atherosclerosis and the development of targeted immunotherapies continues to be an evolving area of research that is rapidly becoming clinically relevant for the 21st century cardiac patient.
Mortality, GBD and Causes of Death, C, Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.
]. Primary and secondary prevention of adverse cardiovascular events remains a critical priority to alleviating morbidity and mortality. Underlying mechanisms behind the development of atherosclerosis are intrinsically tied to immune dysregulation through inflammatory mediators [
]. Multiple pathologic drivers such as pro-inflammatory cytokines, leukocyte recruitment, and inflammatory signaling drive atherogenesis in the vessel wall and systemic inflammation [
]. While excess cholesterol storage is no longer viewed as the singular criteria to develop atherosclerosis, hypercholesterolemia is a permissive factor enabling other risk factors to take effect [
]. Thus, current treatment recommendations to prevent atherosclerotic cardiovascular disease (ASCVD) are targeted to lipid lowering therapy, aspirin therapy, and modification of established risk factors with anti-hypertensives, smoking cessation, and blood glucose control.
Recently, extensive investigative efforts have further detailed the role of inflammation underlying atherosclerosis, establishing biomarkers and delineating mechanisms of immunomodulation [
]. Extensive evidence correlating inflammatory diseases and cardiovascular risk also argues for a common underlying inflammatory pathway. The inflammatory hypothesis of atherothrombosis argues for a dynamic state of immune dysregulation from multiple actors detectable by biomarkers and treatable by immunomodulatory drugs (Fig. 1). Targeting immune mechanisms underlying cardiovascular disease introduces a renewed paradigm to the primary prevention of ASCVD. In this review, treatment avenues that target inflammation are discussed.
Fig. 1Inflammatory pathways in the atherosclerotic process.
Potential treatment targets are depicted in red. In response to certain inciting processes (e.g. endothelial shear stress or hypertension), the endothelium upregulates VCAM-1 and MCP-1, in part via cytokine release from mast cells. As a result, circulating PSGL+/CCR2+ monocytes are recruited into the intimal layer. These monocytes differentiate via Nefrin and M-CSF into macrophages, which internalize oxidized LDL and form foam cells. Th1 cells interact with foam cells via activated CD30 and CD40/CD40L and with APCs via PD-L1/2, thereby releasing pro-inflammatory cytokines such as IFN-gamma, IL-6, IL-12 and TNF. This is counteracted by anti-inflammatory effects of IL-10 and TGF-beta via Treg cells. Activated platelets release MRP-8/14, CD40L and IL-6, which activates TLR 2/4-MyD88 leading to downstream activation of the NFκB pathway. This activates NLRP3 and its associated inflammasome via IL-1 signaling, as well as via the cytokines released from activated Th1 cells. Inflammasome activation has many pro-inflammatory effects, such as activation of caspase, which contributes to foam cell apoptosis and cell necrosis. The resulting lipid-laden cellular debris accumulates in the necrotic core, which forms an atherosclerotic plaque. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
2. Concept of inflammation in atherosclerotic vascular disease
Earlier concepts of the underlying mechanisms of atherosclerosis were largely based on the primary pathophysiologic importance of hypercholesterolemia in the inception of atherosclerotic cardiovascular disease (ASCVD). Atherosclerosis was believed to be a due to deposition of lipid debris in the arterial wall with concomitant proliferation of smooth muscle cells in the sub-intimal layer leading to formation of the atheromatous plaque. Progressive accumulation of a variety of cells and lipid was considered to result in plaque growth, plaque instability and eventually rupture, leading to an acute coronary syndrome. As insights into the contribution of endothelial dysfunction to the atherosclerotic process became evident, so did the realization of the role of inflammation as a key regulator of atherosclerosis progression [
Diabetes, smoking, hypertension, and the metabolic syndrome as well as autoimmune diseases are well known risk factors for ASCVD and are associated with a state of chronic inflammation [
Plasma concentration of C-reactive protein is increased in type I diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation.
]. Although hsCRP is likely not directly involved in the atherosclerotic process, its increase points to a low level systemic inflammatory state. Together with smooth muscle cells, immune and inflammatory cell infiltration was long appreciated in atherosclerotic lesions [
]. Evidence of local adaptive and innate immune activation in atherosclerosis further solidified the concept of an active inflammatory process orchestrating atherosclerosis, supporting the inflammatory hypothesis of atherothrombosis [
3. Basic mechanisms of inflammation in atherosclerosis
3.1 Innate immunity in atherosclerosis
The innate immune system is heavily involved even in the earliest stages of atherosclerosis. The healthy vascular endothelium is relatively resistant to prolonged contact with leukocytes. Exposure to certain known cardiovascular risk factors (e.g. hypertension, hypercholesterolemia, diabetes mellitus, smoking, disruptions in laminar shear stress) stimulates the arterial endothelium to express adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and chemokines such as monocyte chemoattractant protein-1 (MCP-1). These molecules recruit circulating monocytes and dendritic cells into the intimal layer. Upon stimulation by cytokines, such as monocyte-colony stimulating factor (M-CSF) monocytes differentiate into macrophages, the most common cell type in the atheromatous plaque [
]. Macrophages express scavenger receptors on their surface that permit internalization of LDL particles after oxidation. LDL oxidation is a necessary step for binding with macrophage scavenger receptors and therefore can catalyze foam-cell formation. Reactive oxygen species attack double bonds in unsaturated fatty-acids of cholesteryl esters that can generate crosslinks between free amino groups on Lys and Arg residues. These post-translational changes alter their molecular, immunogenic and functional properties. For example, exposure to oxidized LDL particles can elicit an antibody response or activate VCAM-1 expression in endothelial cells, thereby recruiting more leukocytes into the atherosclerotic lesion. Additionally, macrophages are able to imbibe LDL via micropinocytosis and phagocytosis. Eventually, cholesterol uptake overwhelms the cellular cholesterol processing capacity and cholesteryl ester droplets accumulate in the cytosol. When macrophages become overloaded with these cholesteryl esters, they take on a characteristic “foam cell” appearance. Many of these cells undergo apoptosis and the necrotic debris and apoptotic bodies contribute to a necrotic core in the evolving atheromatous lesion.
In the context of the inflammatory hypothesis of atherothrombosis, the IL-1 gene class family plays a critical role. A relative increase in interleukin-1 beta (IL1-β) mediates a pro-inflammatory environment, while a predominance of its counterpart IL-1Ra mediates an anti-inflammatory environment [
Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
]. IL1-β is produced mostly by monocytes and macrophages and circulates systemically. The nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 (NLRP3) intracellular protein complex responds to pathologic signals in order to increase the secretion of IL1-β, subsequently increasing inflammation downstream [
]. Accumulation of cholesterol crystals in the macrophage activates the NLRP3 gene, thereby triggering its associated inflammasome, which allows post-translational modification of the inactive preform of interleukin-1β (IL-1β) into its bioactive molecule [
]. Increased IL1-β results in monocyte and leukocyte adhesion to vascular endothelial cells and stimulates IL-6 that drives the acute phase response with consequent elevation in inflammatory biomarkers such as hsCRP, further inciting chronic inflammation associated with atherosclerosis [
Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
]. For instance, IL-1β has been shown to induce VCAM-1 expression on endothelial cells. In fact, genetic targeting of IL-1β or other molecules in the NLRP3 inflammasome was shown to reduce atherosclerosis in mice [
]. In animal models, decreased IL1-β production was related to a reduction in atherosclerotic lesions, and IL-1Ra null mice develop spontaneous arterial inflammation [
]. Potentially protective in healing infarcts, IL-1Ra is upregulated in those with acute coronary syndromes compared to stable CAD, preceding the release of myocyte necrosis [
Cytokines in acute myocardial infarction: selective increase in circulating tumor necrosis factor, its soluble receptor, and interleukin-1 receptor antagonist.
]. As a result of IL1-β over IL-1Ra predominance creating a waxing and waning pro-inflammatory environment both systemically and in the vessel wall, elevations in inflammatory biomarkers such as hsCRP occur years in advance prior to coronary artery plaque rupture [
Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
Many studies have addressed the role of toll-like receptor (TLR) pathways as an important signaling cascade in atherosclerosis. Results have not been uniform, but in general TLR 2 and TLR4 appear proatherogenic, whereas TLR3, TLR7 and TLR9 appear atheroprotective [
]. Ultimately, these result in downstream activation of the NF-κβ pathway, which regulates expression of many inflammatory molecules identified in atherosclerosis [
P-selectin glycoprotein ligand-1 is highly expressed on Ly-6Chi monocytes and a major determinant for Ly-6Chi monocyte recruitment to sites of atherosclerosis in mice.
]. Ly6Chigh monocytes bind more avidly to activated endothelium and home to atherosclerotic lesions via the chemokine receptor CCR2 than the non-atherogenic Ly6Clow monocyte population. After homing, Ly6Chigh express pro-inflammatory cytokines and matrix metalloproteinases.
Recently, pharmacologic and genetic studies have implicated a role for mast cells in atherosclerosis via IFN-γ and IL-6 signaling [
]. As there are established treatments targeting mast cells, this could have implications for potential repurposing of those drugs for atherosclerotic disease. The high concentration of granulocytes, dendritic cells and activated complement in atheroma implies a potential contribution of these cells to the atherogenic process, but the exact mechanisms still remain unclear [
Finally, considerable crosstalk exists between the molecular precursors involving thrombosis and inflammation. Upon activation, platelets release pro-inflammatory mediators such as myeloid-related protein (MRP)-8/14 CD40 ligand (CD154) and IL-6 [
Mounting evidence has supported an important role for the adaptive immune system in atherosclerosis. Human atherosclerotic lesions contain largely effector-memory T cells, of which the majority are CD4+ and the rest is CD8+. Atheroma T cells are mostly T helper-1 (Th1) cells and upon activation by antigens such as oxidized LDL and heat shock protein (HSP)60 via dendritic cells, secrete IFN-γ and tumor necrosis factor (TNF), both promoting atherogenesis. Th17 cells, a subpopulation of T cells modulates lesion formation and composition, but seems to lack a key role in atherosclerosis [
]. Treg cells exert their anti-atherosclerotic effect, at least in part, by counteracting effector T cells, as well as extra-atheroma effects on cholesterol metabolism [
]. A potential avenue for drug discovery could be costimulatory or coinhibitory targets in T cell activation. Clinically available drugs include inhibitors of the B7 costimulatory pathway (which inhibits T cells response in autoimmune disease or renal allograft rejection) or blockers of the PD-L1/L2 coinhibitory pathway (decreases inhibition of T cells in cancer) [
]. These drugs are predicted to aggravate atherosclerosis, but further exploration could yield clinically useful drugs targets.
Converging evidence points to a modulating role of humoral immunity in atherosclerosis. Splenectomy, and the resulting elimination of a subset of B cells, promotes atherosclerosis, whereas global B cell depletion with anti-CD20 antibody reduces ASCVD burden [
]. Ongoing studies will have to elucidate whether this is also feasible in humans.
4. Targeting inflammation to reduce ASCVD events
Appreciation of the pivotal contribution of inflammation in atherosclerosis opens up a new treatment paradigm, as many potential targets for ASCVD drug therapy can be investigated, including the repurposing of existing drugs. The JUPITER trial showed that individuals without significant hypercholesterolemia (LDL <120 mg/dL) but elevated hsCRP (>2 mg/L) benefit from statin treatment [
]. hsCRP is an inflammatory biomarker that is synthesized in the liver in response to cytokines such as IL-6. It is a robust marker of level systemic inflammation, relatively easy to measure, biologically stable and has a long half-life. Mechanistically, hsCRP is likely not involved or derived from the atherosclerotic plaque, but is downstream to inflammation within the plaques.
As outlined above, inflammation is a process that leads to acute plaque progression and acute coronary events, independent of cholesterol levels. Statins also possess anti-inflammatory properties as they reduce CRP levels, and are currently under investigation in the treatment of various inflammatory diseases [
]. In patients with intermediate cardiovascular risk profiles, hsCRP can be used to restratify patients into risk categories. In fact, HsCRP has been incorporated into the Reynold's risk score, a population based risk calculator [
]. Hsp60, a cytosolic chaperonin autoantigen, is expressed in response to endothelial cell stress, enabling an immune response that is involved in the development of atherosclerosis [
]. With both anti-oxLDL and anti-oxHsp60 antibodies, the level of antibodies correlate with the degree of atherosclerotic lesion burden in mice models, clinical ASCVD events in humans, and with hypercholesterolemia in both mice models and humans [
IL1-β induced pro-inflammatory environment has been implicated as a primary driver in a number of inflammatory diseases including diabetes mellitus type 2, gout, psoriasis, inflammatory arthritis, inflammatory bowel disease, Muckel-Wells syndrome, and cryopyrin-associated periodic syndrome [
]. Furthermore, the link between IL-1 and atherosclerosis has been extensively investigated. The monoclonal antibody, Canakinumab, specifically targets and neutralizes IL1-β by blocking the interaction between IL1-β and its receptors. Canakinumab has negligible effects on the lipid profile and is thus an ideal immunomodulatory drug to test the inflammatory hypothesis of atherothrombosis [
Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
]. In the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS), post-myocardial infarction patients with CRP levels greater than 2 mg/L, despite guideline-based medical therapy including statins, were randomized to placebo or to therapy with canakinumab (50 mg, 150 mg, or 300 mg subcutaneously every 3 months) [
Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
]. The primary outcome measure was the incidence of recurrent major cardiovascular events (nonfatal MI, nonfatal stroke, or cardiovascular death). Secondary outcomes included safety, total mortality, and vascular events (ie unstable angina requiring revascularization), and exploratory endpoints included incidence of deep venous thrombus/pulmonary embolism, supraventricular tachycardia, hospitalizations for CHF, PCI/CABG, changes in lipid markers, and changes in hsCRP. In over 17,000 adults enrolled, hsCRP levels decreased after 2 years by 26% at 50 mg, 37% at 150 mg, and 41% in the 300 mg canakinumab treated groups [
]. The primary endpoint was achieved with a reduction in recurrent cardiovascular events; hazard ratio (HR) of 0.85 (p = 0.021, 95% CI 0.84–0.98) in the 150 mg group and HR 0.86 (p = 0.031, 95% CI 0.75–0.99) in the 300 mg group [
]. While there was no significant difference in all-cause mortality, there was a significant reduction in incident malignancies including incident lung cancers [
]. In subgroup analysis, participants with moderate to severe CKD with a glomerular filtration rate greater than 30/ml/min/1.73 m2 who achieved hsCRP levels <2 mg/L had a 31% reduction in major adverse CV events [
]. Furthermore, there was an increase in risk of fatal infection in the canakinumab group. Ultimately, CANTOS demonstrated that IL1-β inhibition can reduce recurrent cardiovascular events in a secondary prevention cohort, proving the importance of inflammation in the pathogenesis of atherothrombosis and the role of IL1-β in plaque generation [
IL-1Ra antagonist, Anakinra, blocks endogenous IL-1, and can thus inhibit the downstream sequelae of IL-1-mediated inflammation. Anakinra is currently approved for the treatment of inflammatory disorders including rheumatoid arthritis. In a randomized, double-blind controlled trial, patients with rheumatoid arthritis were initiated on anakinra versus placebo plus prednisolone. After thirty days, the anakinra group demonstrated improved coronary flow reserve, left ventricular function and endothelial function and had reduction in endothelin-1 and IL-6 levels [
]. In the MRC-ILA-HEART study, 182 patients with a recent non-ST elevation MI were randomized to treatment with anakinra or placebo. Despite a significant reduction in hsCRP and IL-6 after 14 days, there was an increase in adverse events in the anakinra treated group after 1 year [
The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study.
]. To further understand the complex link between the development of atherosclerosis, acute coronary syndrome, and IL-1 receptor antagonism, additional trials should be undertaken.
5.1.3 Interleukin-6 (IL-6) inhibitors
IL-6 signaling initiates a downstream pro-inflammatory state, resulting in an increase in hsCRP, fibrinogen, and other acute phase reactants, and has been implicated in a casual association with coronary heart disease [
]. Furthermore, IL-6 levels rise in response to IL1-β stimulation and in other pro-inflammatory states. The IL-6 inhibitor, tocilizumab, is currently approved to treat rheumatoid arthritis. Observational data showed a reduction in pulse wave velocity in patients with rheumatoid arthritis treated with tocilizumab after three months of therapy [
The impact of newer biological disease modifying anti-rheumatic drugs on cardiovascular risk factors: a 12-month longitudinal study in rheumatoid arthritis patients treated with Rituximab, abatacept and tociliziumab.
]. In the randomized, controlled MEASURE trial, 132 patients with rheumatoid arthritis underwent IL-6 inhibition with tocilizumab + methotrexate versus placebo + methotrexate. In the tocilizumab + methotrexate group, patients had elevated LDL-C, triglycerides, and median total cholesterol, but had favorable changes with less pro-inflammatory HDL particle composition, reduction in Lp(a), and no change in pulse wave velocity. Thus, IL-6 inhibition in overall role in atherosclerosis remains unclear [
Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis.
TNFα plays an essential role in adaptive immunity and in the promotion of atherogenesis. Evidence of TNF alpha production from monocytes, macrophages, and smooth muscle cells has been demonstrated in intimal plaques [
]. TNFα inhibitors such as infliximab, etanercept and adalimumab are antibodies that reduce inflammation in both autoimmune diseases such as rheumatoid arthritis and in atherosclerosis [
Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis.
]. TNF blockade results in multiple effects: TNFα downregulation, inhibition of expression of other pro-inflammatory cytokines including IL-1β, IL-6, IL-8, MCP-1, GM-CSF, VEGF and reduction of matrix-degrading enzymes which classically are found in unstable plaque [
]. In a retrospective cohort of 2101 patients with rheumatoid arthritis, patients with TNFα inhibitor and methotrexate compared to methotrexate had a decreased risk of CAD [
]. In fact, across 13 cohort studies including 106,202 participants demonstrated a significant reduction in the risk of adverse cardiovascular events, MI, and CVA in patients who were given anti-TNFα therapy compared to those given disease-modifying anti-rheumatic drugs (DMARDs) [
]. Conversely, 3 randomized controlled trials including 2216 participants did not show cardiovascular benefit when comparing anti-TNFα therapy to DMARDs [
]. Furthermore, in a different study population of heart failure patients (NYHA class III-IV symptoms and an ejection fraction of less than 35%), the ATTACH trial showed that infliximab at 5 mg/kg did not have any beneficial cardiovascular effects, and infliximab at 10 mg/kg was associated with the progression of heart failure [
Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy against Congestive Heart Failure (ATTACH) trial.
]. This may suggest that TNFα during later stages of cardiomyopathy may play a protective role, potentially preventing apoptosis, increasing nitric oxide production, and decreasing beta-adrenergic stimulation [
Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy against Congestive Heart Failure (ATTACH) trial.
]. A comprehensive understanding of TNF blockade's spectrum of activity in cardiovascular disease, from clinical benefit to potential adverse effects, remains unclear and warrants further investigation.
5.1.5 Chemokine CC motif ligand 2 (CCL2) inhibitors
CCL2, also known as monocyte chemotactic protein-1 (MCP-1) is found in atherosclerotic plaques on immune cells and monocytes, stimulating endothelial-monocyte attachment to chemokine CC receptors (CCR2) [
Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region.
]. In the Orbofan in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction 16 (OPUS-TIMI 16) trial, CCR2 levels in patients with an acute coronary syndrome predicted future adverse cardiovascular events [
]. In a double-blind, placebo-controlled, randomized trial, MLN1202, a monoclonal antibody that interrupts CCL2 binding by blocking CCR2, decreased circulating hsCRP levels in patients with risk factors for, or presence of coronary artery disease [
Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region.
]. OxLDL triggers inflammation through altering its identification and internalization from LDL receptors to scavenger receptors found on vascular cell walls, dentritic cells, and macrophages [
]. Cardioprotective benefit from anti-oxLDL IgM antibodies have been shown in animal models. In mice models, passive immunization with IgM oxLDL antibodies reduced plaque volume formation [
]. Due to these anti-atherogenic properties, the use of IgM or IgG4 antibodies directed towards oxLDL has been proposed. Preliminary studies have demonstrated inconsistent results with regards to an association of oxLDL and ASCVD events and with treatment response with antibody therapy. While a meta-analysis of 12 studies did show increased circulating oxLDL associated with clinical ASCVD events, in other studies comprised of a small population of CVA patients and patients with established CAD, oxLDL antibodies did not relate to stroke severity or outcome or presence and severity of CAD, respectively [
]. While some anti-oxLDL antibodies may be atheroprotective, the role for oxLDL antibodies in preventing ASCVD requires further investigation.
5.2.2 PD-1/PD-L1 agonism
PD-1 is a co-inhibitory molecule that binds to PD-L1 found on antigen presenting cells and vascular tissue beds, promote anti-inflammatory cytokine production, potentially counterbalancing mechanisms underlying atherosclerosis [
]. Because of the rising use of PD-1 inhibition and PD-L1 inhibition in the immunotherapy of a number of cancers, further study on the increased cardiovascular risk should be undertaken.
5.3 Anti-metabolites
5.3.1 Methotrexate
Methotrexate is a folate antimetabolite that interferes with DNA synthesis and repair. Via IL1ra upregulation, decreases expression of pro-inflammatory Th1 cytokines, COX-2 inhibition, neutrophil chemotaxis inhibition, it has an established immunomodulatory effect, reducing TNF, IL-6, and CRP levels [
Effects of treatment with etanercept versus methotrexate on sleep quality, fatigue and selected immune parameters in patients with active rheumatoid arthritis.
]. Observational data suggests that methotrexate may reduce adverse vascular events in patients treated with inflammatory arthropathies, including rheumatoid arthritis and psoriatic arthritis [
]. Whether these potential anti-inflammatory properties of methotrexate would lead to prevention of adverse cardiovascular events needed to be studied. The Cardiovascular Inflammation Reduction trial (CIRT) aims to randomize 7000 patients with a prior myocardial infarction and either diabetes mellitus type 2 or metabolic syndrome to placebo or low dose methotrexate (15–20 mg/week) therapy [
]. Subjects will be followed up for 3–5 years to determine the incidence of the primary composite end point of nonfatal MI, nonfatal stroke, and cardiovascular death and secondary end points of all-cause mortality, primary end points plus congestive heart failure exacerbation requiring hospitalization and/or coronary revascularization and/or all-cause mortality, incidence of diabetes type II, and net clinical benefit versus harm [
]. Due to these anti-inflammatory properties, cholchicine has been a hallmark therapy for gout, pericarditis, Bechet's disease, and familial Mediterranean fever. Colchicine has been implicated in affecting NLP3 activation during atherogenesis, potentially blocking NLRP3 inflammasome and consequently, IL1-β production [
Effect of colchicine (0.5 mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease.
]. A Cochrane review analyzing 4992 patients in 39 trials showed that cardiovascular death and myocardial infarction may be reduced at the expense of increased gastrointestinal intolerance [
In the prospective, randomized low dose colchicine (LoDoCo) trial, 532 patients were followed for a median of 3 years in an intention to treat analysis [
]. Two trials underway with larger enrollments, LoDoCo2 and COLCOT will provide additional data on colchicine and its impact on CV event rates. The prospective, randomized LoDoCo2 trial has an target of 4230 participants and will look at a composite of cardiovascular death, non-fatal ACS, or non-fatal stroke [
The LoDoCo2 Trial: a randomised controlled trial on the effect of low dose Colchicine for secondary prevention of cardiovascular disease in patients with established, stable coronary artery disease.
in: Austrialian New Zealand Clinical Trials Registry. 2014
]. The Colchicine Cardiovascular Outcomes trial (COLCOT) has an estimated 4500 participant enrollment in a prospective, randomized clinical trial examining the impact of colchicine 0.5 mg/day versus placebo in preventing cardiovascular death, stroke, acute MI, resuscitated cardiac arrest, and hospitalization for angina requiring coronary vascularization [
Leukotrienes are synthesized by bone marrow-derived cells (neutrophils, monocytes, macrophages, dendritic cells, and mast cells) and comprise of pro-inflammatory mediators of the eicosanoid family [
]. Specifically, 5-lipoxygenase and its activating protein may increase susceptibility to atherosclerosis by promoting activation of other pro-inflammatory molecules in the intima, resulting in increased vascular permeability, increased sub-intimal oxidized LDL uptake, and localized vascular inflammation [
]. Leukotrienes have been implicated in a number of inflammatory conditions including asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and psoriasis [
]. While 5-lipoxygenase inhibition with Atreleuton resulted in reduction in hsCRP levels and in non-calcified coronary plaque volume, a phase II, randomized, double-blinded, placebo-controlled study showed no reduction in vascular inflammation measured by FDG-PET or hsCRP levels in patients with an acute coronary syndrome [
A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome.
]. An inhibitor of 5-lipoxygenase activating protein (FLAP), Veliflapon has been studied in patients with a history of myocardial infarction. In a randomized, controlled trial, 191 patients with an hight-risk genetic variant in the FLAP gene or the in leukotriene A4 hydroxylase gene were given Veliflapon versus placebo. Some cardiac biomarkers, including CRP, myeloperoxidase, and serum amyloid A were reduced, while Lp-PLA2 and LDL were increased [
]. Through hydrolysis of oxidized phospholipids, PLA2 triggers the release of oxidized fatty acids and lysophosphatidylcholine in HDL, modifying mildly oxidized low density lipoprotein (MM-LDL) and creating a pro-inflammatory, pro-atherogenic environment [
]. Lp-PLA2, also known as platelet-activating-factor acetylhydrolase (PAF-AH), is typically bound to lipoproteins such as HDL, while secretory PLA2 (sPLA2) is an acute phase reactant made in the liver [
]. Lp-PLA2 mass and activity have been predictive of coronary heart disease, stroke, and mortality in 79,036 participants enrolled in 32 prospective studies [
Darapladib, a selective Lp-PLA inhibitor, has been extensively studied in multiple prospective, double-blinded randomized controlled trials. In the Integrated Biomarkers and Imaging Study-2 (IBIS-2) trial, 12 months of therapy with darapladib did not reduce coronary plaque volume but did achieve a secondary endpoint, the prevention of necrotic core expansion [
]. While Lp-PLA2 activity was decreased by nearly 65% in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial, there was no change in cardiovascular death, myocardial infarction, or stroke over 1.5 years in 15,828 patients with stable coronary artery disease randomized to darapladib versus placebo [
Lipoprotein-associated phospholipase A2 activity is a marker of risk but not a useful target for treatment in patients with stable coronary heart disease.
]. In the SOLID-TIMI 52 study, 13,026 patients were given darapladib within 30 days of hospitalization for secondary prevention after an acute coronary event [
]. sPLA2 inhibition with Varespladib has also undergone extensive scrutiny. In the Varespladib and cardiovascular events in patients with an acute coronary syndrome (VISA 16) trial, varespladib improved lipid and inflammatory markers, but did not reduce overall cardiovascular event rate but increased the risk of myocardial infarction, demonstrating potential harm with immune modulation of certain targets [
]. Thus, inhibition of pro-inflammatory PLÁ2 enzymes has not produced any tangible benefit in patients with stable coronary disease or with a recent acute coronary syndrome.
5.7 Succinobucol
LDL oxidation plays a pivotal role in oxidative stress, inflammation, and the generation of atherosclerotic plaques. Thus, LDL metabolism serves as an attractive target for immunomodulation. Succinobucol has anti-inflammatory and anti-oxidant properties and decreases development of atherosclerosis in animal models [
]. In the ARISE trial, 6144 patients were randomized to receive succinobucol or placebo, but there was no reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, unstable angina, coronary revascularization, or resuscitated cardiac arrest [
]. However, the risk of the secondary endpoint, a composite of cardiovascular death, cardiac arrest, myocardial infarction, or stroke, was reduced by 19% and patients were noted to have a 64% reduction in the risk of new-onset diabetes. Further studies are needed to further delineate the impact of succinobucol on cardiovascular events.
6. Conclusions
Prevention of cardiovascular disease remains a priority. Mechanisms of inflammation underlying CVD have been well-established, and a select group of patients exhibiting immune dysfunction would greatly benefit from potential anti-inflammatory therapies. To identify these patients, systemic markers of inflammation, including hsCRP, would provide considerable clinical utility to establish those patients at an elevated residual inflammatory risk. While some current therapeutic options mitigate traditional cardiovascular factors, future therapies may also focus on underyling mechanisms for immune dysregulation to treat atherosclerosis. Data supporting the role for immune dysregulation underlying atherosclerosis is becoming better understood and is yielding novel therapeutic targets for clinical trials. While some immune based therapies have failed to show benefit in atherosclerosis, findings from the CANTOS trial have provided pivotal data to support the role of inflammation in atherothrombosis. Understanding these mechanisms in the appropriate clinical context to target therapy is critical, as some therapies, such as NSAIDs in coronary artery disease and TNF blockade in heart failure, have an adverse effect on cardiovascular outcomes. Furthermore, whereas CANTOS has shown signals with the risk of increased infection from an impaired immune response and the potential benefit in cancer prevention, a comprehensive understanding of the impact of immune based therapies will require further study.
Conflicts of interest
The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
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Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
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The impact of newer biological disease modifying anti-rheumatic drugs on cardiovascular risk factors: a 12-month longitudinal study in rheumatoid arthritis patients treated with Rituximab, abatacept and tociliziumab.
Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis.
Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis.
Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy against Congestive Heart Failure (ATTACH) trial.
Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region.
Effects of treatment with etanercept versus methotrexate on sleep quality, fatigue and selected immune parameters in patients with active rheumatoid arthritis.
Effect of colchicine (0.5 mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease.
The LoDoCo2 Trial: a randomised controlled trial on the effect of low dose Colchicine for secondary prevention of cardiovascular disease in patients with established, stable coronary artery disease.
in: Austrialian New Zealand Clinical Trials Registry. 2014
A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome.
Lipoprotein-associated phospholipase A2 activity is a marker of risk but not a useful target for treatment in patients with stable coronary heart disease.
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