Atherosclerosis and inflammation. New therapeutic approaches

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"documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2020;155:254-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial article" "titulo" => "Ultrasound and elastography in Sjögren's syndrome" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "254" "paginaFinal" => "255" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Ecografía y elastografia en el diagnóstico de síndrome de Sjögren" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Hèctor Corominas, Juanjo de Agustín" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Hèctor" "apellidos" => "Corominas" ] 1 => array:2 [ "nombre" => "Juanjo" "apellidos" => "de Agustín" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775320302888" "doi" => "10.1016/j.medcli.2020.04.021" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320302888?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020620303764?idApp=UINPBA00004N" "url" => "/23870206/0000015500000006/v2_202102250949/S2387020620303764/v2_202102250949/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Atherosclerosis and inflammation. New therapeutic approaches" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "256" "paginaFinal" => "262" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Juan Pedro-Botet, Elisenda Climent, David Benaiges" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Juan" "apellidos" => "Pedro-Botet" "email" => array:1 [ 0 => "86620@parcdesalutmar.cat" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Elisenda" "apellidos" => "Climent" ] 2 => array:2 [ "nombre" => "David" "apellidos" => "Benaiges" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Lípidos y Riesgo Vascular, Servicio de Endocrinología y Nutrición, Hospital del Mar, Universidad Autónoma de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Arteriosclerosis e inflamación. Nuevos enfoques terapéuticos" ] ] "textoCompleto" => "IntroductionAtherosclerosis is a disease that has affected humans for millennia, as evidenced by the degenerative changes found in the arterial tree of 47 out of 137 mummies from 4 different geographic areas (Egypt, Peru, the ancestral peoples of southwestern America and the Unangan from the Aleutian Islands),<a class="elsevierStyleCrossRef" href="#bib0005">1</a> vascular lesions that do not differ from those currently observed. On the other hand, evidence from experimental and human models of atherosclerosis, from biomarker studies and more recently from clinical intervention trials has provided over time further clarification of the mechanisms involved in atherogenesis. So, in the XIX century, German pathologist Rudolf Virchow<a class="elsevierStyleCrossRef" href="#bib0010">2</a> already recognized the inflammatory nature of atherosclerosis: “… Inflammation of the arterial inner layer is the starting point of the so-called atheromatous degeneration…”. Unfortunately, for more than a century this theory gave way to the view of atheroma as a passive deposit of lipids.It is now well known that atherosclerosis is a chronic low-grade inflammatory disease that occurs in the artery wall and is initiated primarily in response to endogenously modified elements, especially oxidized low-density lipoproteins (OxLDL), which stimulate innate and adaptive immune responses. Intracellular cholesterol accumulation is the trigger for the inflammasome response leading to the production of inflammatory mediators such as interleukin (IL)-1β. The innate response begins with the activation of endothelial cells in the arterial wall and monocytes/macrophages; the adaptive immune response then occurs to a series of potential antigens presented to effector T lymphocytes by antigen presenting cells, such as dendritic cells. Both innate and adaptive immune responses are key in the onset and development of atherosclerosis. It should be said that the cellular and molecular interactions in atherogenesis do not differ from those that occur in chronic inflammatory diseases such as rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Almost all immunoinflammatory system cell types, as well as many pro and anti-inflammatory cytokines and chemokines, have also been identified in atherosclerosis.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>A process called efferocytosis, or the efficient clearance of apoptotic cells by phagocytes, ensures resolution of inflammatory responses.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> This involves the recognition of certain signals, such as the exposure of phosphatidylserine in apoptotic cells to their respective macrophage receptors, as well as to bridging molecules that mediate binding. Opposite signals for non-phagocytosis, such as CD47 expression, also play a role and influence atherogenesis. Apoptotic cell uptake is associated with increased expression of anti-inflammatory cytokines (transforming growth factor-β and IL-10), as well as a decrease in the expression of proinflammatory cytokines (IL-8 and IL-1β) by macrophages. Thus, efficient efferocytosis protects from atherogenesis by removing cellular debris and creating an anti-inflammatory medium. Furthermore, the uptake of cellular debris favours the production of lipid mediators, such as lipoxins, resolvins and maresins, which actively participate in the resolution of inflammatory processes. In chronic inflammation, the proinflammatory environment disrupts the expression of molecules that regulate efferocytosis, so that OxLDL particles compete for uptake by macrophages in atherosclerotic lesions.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> As a result, the efferocytosis becomes defective and the resolution of the inflammation, driven primarily by the modified LDL particles, deteriorates. Under these conditions, apoptotic cells accumulate with the consequent secondary necrosis and release of molecules, which together have been called damage-associated molecular patterns or warning signs that further spread inflammation.A considerable number of acute phase proteins have been recognized during inflammatory processes, with C-reactive protein (CRP) being the most useful serum marker, despite its low specificity for any particular inflammatory process, including atherosclerosis. High sensitivity CRP determination was developed to detect very low levels of this protein and to allow a more accurate measurement of chronic inflammation compared to standard CRP. The association between high-sensitivity plasma CRP levels and the risk of cardiovascular events is debated, as there is clinical evidence in favour and against. Finally, large cohort genetic studies have not confirmed that chronically elevated high-sensitivity CRP increases the risk of vascular events.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Despite the above, some clinical practice guidelines have suggested the inclusion of high-sensitivity CRP alongside traditional vascular risk factors to improve prognostic information, especially in patients with intermediate cardiovascular risk.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Impact of lipid-lowering drug treatment on inflammationStatins, in addition to inhibiting HMG-CoA reductase, an enzyme that limits intracellular cholesterol synthesis, decrease CRP secretion by hepatocytes,<a class="elsevierStyleCrossRef" href="#bib0045">9</a> and in certain forums it has been pointed out that the benefits of statin therapy are related to the reduction of cholesterol levels and inflammation. The study Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)<a class="elsevierStyleCrossRef" href="#bib0050">10</a> in subjects in primary prevention with a concentration of LDL cholesterol < 130 mg/dl (3.4 mmol/l) and chronically elevated CRP (>2 mg/l) showed that statin treatment significantly reduced the occurrence of cardiovascular events.In addition to improving the lipid profile, two new lipid-lowering drugs, bempedoic acid and pemafibrate, decrease the plasma concentration of high-sensitivity CRP to the same extent as statins.<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a> The first is a new oral molecule, a prodrug that requires activation of the long-chain acyl-coA synthetase 1 enzyme, which is present in the liver but absent in other tissues, which reduces LDL cholesterol by inhibiting ATP-citrate lyase.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Pemafibrate is a new selective modulator of peroxisomal proliferator-activated receptors (PPAR-α) which effectively lowers triglyceride levels and increases HDL cholesterol levels more significantly than fenofibrate, with greater liver and kidney safety.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>Other blood cholesterol lowering drugs, such as ezetimibe and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, lead to additional significant reductions in cardiovascular events when co-administered with statins, but without modifying plasma concentrations of high-sensitivity CRP.<a class="elsevierStyleCrossRefs" href="#bib0065">13,14</a>Reduction of inflammation as a therapeutic strategy in cardiovascular preventionThe lipid theory initially postulated by N. Anichkov, a pathologist at the Military Medical Academy in St. Petersburg has provided the traditional approach to understanding atherosclerosis. LDL cholesterol is undoubtedly a causal factor of atherosclerosis<a class="elsevierStyleCrossRef" href="#bib0025">5</a> and has become the main therapeutic objective of cardiovascular prevention.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> However, despite currently effective drugs, such as statins, ezetimibe, and PCSK9 inhibitors, used alone or as combination therapy, we still face an unacceptably high rate of cardiovascular events. Therefore, once atherosclerosis is recognized and accepted as a chronic inflammation of the arterial wall, it is easy to understand that anti-inflammatory strategies have emerged for the prevention of atherosclerosis complications.Conventional anti-inflammatory drugsAnti-inflammatory drugs, such as glucocorticoids, non-steroidal anti-inflammatory drugs, and cyclooxygenase (COX)-2 inhibitors, are highly effective in specific situations, such as acute inflammation or symptomatic flares of autoimmune diseases. In this clinical context, the adverse reactions of these drugs are minimal due to short-term use, or even accepted due to the high benefit/risk ratio in symptomatic diseases.In a population-based case-control study analysing the effects of glucocorticoids in more than 100,000 patients with chronic inflammatory diseases, an increase in cardiovascular events was found in those treated, regardless of timing and steroids dose (single or cumulative).<a class="elsevierStyleCrossRef" href="#bib0080">16</a> This may be due in part to the negative impact of glucocorticoids on cardiovascular risk factors, with the usual changes in the lipid profile, poor control of blood pressure, weight gain, and insulin resistance. Apart from these harmful effects, the administration of prednisolone encapsulated in lysosomal nanoparticles, as an anti-inflammatory drug directed against atheroma plaque, has been found to exacerbate atherosclerosis.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Selective COX-2 inhibitors are highly effective in reducing arthritic pain. However, the cardiovascular alert detected with rofecoxib<a class="elsevierStyleCrossRef" href="#bib0090">18</a> led to a re-evaluation of this therapeutic class. A non-significant increase in cardiovascular risk was found with ibuprofen and diclofenac compared to naproxen,<a class="elsevierStyleCrossRef" href="#bib0095">19</a> and later, the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) study in more than 27,000 subjects with arthritis concluded that celecoxib, at moderate doses, was not inferior to ibuprofen or naproxen in cardiovascular safety.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> In a sub-analysis focusing on high-risk cardiovascular patients followed for a composite of severe cardiovascular, gastric, and renal events, as well as non-cardiac death, celecoxib showed a more favourable safety profile than naproxen or ibuprofen when administered without aspirin.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>Therapies against specific inflammatory mediatorsAs a result of the large number of inflammatory mediators involved in atherogenesis, multiple pathways have been identified as potential targets for cardiovascular prevention. Globally, most clinical trials directed against specific targets, such as OxLDL particles,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> the segregated phospholipases A2 and associated with lipoproteins (sPLA2 and LpPLA2),<a class="elsevierStyleCrossRefs" href="#bib0115">23–25</a> selectin P,<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> mitogen-activated protein kinases p38<a class="elsevierStyleCrossRef" href="#bib0140">28</a> and even the IL-1β anakinra inhibitor<a class="elsevierStyleCrossRefs" href="#bib0145">29,30</a> have not been able to demonstrate cardiovascular benefits (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>ColchicineColchicine, derived from the plant Colchicum autumnale (“meadow saffron”), is another drug widely used in the treatment of inflammatory conditions. Thus, for example, it has become the conventional treatment for acute pericarditis, by avoiding the rebound phenomenon of glucocorticoids. Colchicine has anti-inflammatory properties as it promotes microtubule disruption, inhibiting neutrophil chemotaxis, impairing the functionality of the inflammasome, and blocking cytokine production.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> In a cohort study, its use in gout patients was associated with a 49% reduction in cardiovascular events and 73% reduction in all-cause mortality.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> The study Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo)<a class="elsevierStyleCrossRef" href="#bib0165">33</a> pioneered the use of colchicine in the secondary prevention of cardiovascular disease. This open-label, placebo-controlled trial which randomized 532 patients with stable coronary heart disease to colchicine 0.5 mg/day versus control, showed a highly significant reduction in the rate of cardiovascular events during a 3-year follow-up. More recently, clear signs of stabilization of the atheroma plaque was observed by coronary computed tomography in patients with acute coronary syndrome treated with colchicine 0.5 mg/day at one year of follow-up. This was attributed to the anti-inflammatory properties of colchicine, as demonstrated by the reductions in the CRP.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> These promising results have generated 4 large-scale investigations to confirm the possible cardiovascular benefits of colchicine. Among these, the Colchicine Cardiovascular Outcomes Trial (COLCOT),<a class="elsevierStyleCrossRef" href="#bib0175">35</a> designed to assess the cardiovascular effects of colchicine at doses of 0.5 mg/day in 4,745 patients with a recent myocardial infarction, demonstrated a reduction in the composite primary endpoint consisting of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or emergency hospitalization for angina leading to 23% coronary revascularization. This study recorded a significant increase in the number of pneumonia cases in the active treatment arm. In general, at the usual doses, colchicine causes gastrointestinal side effects that cause discontinuation of the medication in more than 10% of patients. The LoDoCo2<a class="elsevierStyleCrossRef" href="#bib0180">36</a> (Registry number: ACTRN 12614000093684), a randomized controlled trial evaluating the effect of low-dose colchicine in patients with stable ischemic heart disease, has already recruited more than 4,000 patients.CanakinumabThe Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS)<a class="elsevierStyleCrossRef" href="#bib0185">37</a> tested a specific anti-inflammatory treatment, a human monoclonal antibody that inhibits IL-1β, at doses of 50, 150 and 300 mg. In patients with prior myocardial infarction, under optimal medical treatment and chronic high levels of high-sensitivity CRP, canakinumab decreased the concentration of high-sensitivity CRP and the rate of cardiovascular events compared to placebo in a dose-dependent manner, regardless of lipid profile. The researchers pre-specified 2 complementary analyses; in the first, they showed a significant decrease in cancer mortality in the canakinumab group, with a lower incidence of lung cancer at doses of 150 and 300 mg.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> In a second analysis, they determined which subgroup of patients benefited the most from treatment with canakinumab, based on the degree of reduction in high-sensitivity CRP. In this sense, reaching a high-sensitivity CRP < 2 mg/l was associated with a 31% reduction in cardiovascular and all-cause mortality compared to the placebo group.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Lately, 2 more subanalyses of the CANTOS study have been published. None of the canakinumab doses used was accompanied by an increase in new-onset diabetes or a worsening of the levels of glycated hemoglobin.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> The other analysis compared 1,872 patients with glomerular filtration < 60 ml/min/1.73 m2 with the remaining ∼8,000 patients included in CANTOS.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> Canakinumab reduced the number of serious cardiovascular events in patients with chronic kidney disease, and was particularly effective in those who achieved high-sensitivity CRP < 2 mg/l after the first dose of the drug; in these there was a decrease in the number of cardiovascular episodes, as well as cardiovascular and all-cause mortality.The CANTOS study was the first to highlight the positive correlation between high-sensitivity CRP and cardiovascular events, where the lower levels of high-sensitivity CRP achieved were related to a lower risk of future cardiovascular events. However, some aspects of the study deserve additional comment. The reduction in cardiovascular risk in absolute terms was modest (0.64 per 100 person-years); there was a small, but relevant, risk of serious and fatal infections in the Canakinumab group, and the estimated cost of treatment was about $200,000 a year. It should also be stressed that canakinumab treatment has not been tested against statins combined with ezetimibe and/or PCSK9 inhibitors, so the question of residual vascular risk in patients with elevated high-sensitivity PCR and very low LDL cholesterol concentrations and, ultimately, whether treatment with an anti-IL-1β monoclonal antibody would be beneficial in these cases, remains open. Furthermore, all currently recommended lipid-lowering drugs, including PCSK9 inhibitors, have demonstrated beneficial effects on the composition and regression of the atheromatous plaque, results not available for treatment with canakinumab. This undoubtedly led the Food and Drug Administration to decline the approval of canakinumab for cardiovascular risk reduction based on the data from the CANTOS study.In addition to IL-1β, its sister isoform, IL-1α, exercises many of the same actions,<a class="elsevierStyleCrossRef" href="#bib0210">42</a> but with considerably different cell biology and biochemistry. In this sense, IL-1α does not require inflammasome activation in order to exercise its biological activity, it signals through contact or acts at noticeably short distances, since it is mainly associated with cell surface. Experimental evidence supports the causal role of IL-1α in experimental atherosclerosis,<a class="elsevierStyleCrossRef" href="#bib0215">43</a> and an antibody (xilonix) that neutralizes the human IL-1α is available for clinical use.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>MethotrexateFolic acid antagonist methotrexate blocks the synthesis of purines and pyrimidines by inhibiting key enzymes such as dihydrofolate reductase and thymidylate synthetase. In addition, it reduces the proliferation of antigen-dependent T cells and inhibits adenosine deaminase and adenosine monophosphate deaminase, with the consequent release of adenosine, a molecule with anti-inflammatory properties. At the same time, it seems to have antiatherogenic properties, attributed to the activation of the adenosine A2A receptor, which leads to an improvement in reverse cholesterol transport and a decrease in the formation of foamy cells by THP-1 macrophages.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>Observational studies of patients with rheumatoid arthritis and psoriatic arthritis receiving low-dose methotrexate had reported fewer cardiovascular events than those receiving other therapies or placebo. For this reason, methotrexate was tested as an anti-inflammatory strategy in the Cardiovascular Inflammation Reduction Trial (CIRT)<a class="elsevierStyleCrossRef" href="#bib0230">46</a> carried out in collaboration with the National Heart, Lung, and Blood Institute and designed in parallel to the CANTOS studio. Very low doses of methotrexate were assigned (10 mg/week) versus placebo in 7,000 patients with stable ischemic heart disease. The study was discontinued due to lack of efficacy after a 2.3-year follow-up. At that dose and in a non-rheumatological population, methotrexate had no effect on IL-6 concentrations or high-sensitivity CRP, which could explain the neutral results of the trial. Also, the baseline level of inflammation in the CRIT study population was in a low-risk area (high-sensitivity CRP 1.6 mg/l).HydroxychloroquineHydroxychloroquine is used in the treatment of certain autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, as well as in the prevention and treatment of certain types of malaria. It exerts its immunomodulatory properties through inflammatory pathway suppression by preventing activation of the Toll-type receptor, which is necessary for expression of interferon-regulated genes and for production of TNF-α, a major component of the cell-mediated inflammatory response.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>High-dose hydroxychloroquine therapy (400 mg/day) has been independently associated with a 56.8% reduction in the risk of cardiovascular morbidity in patients with rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> In a retrospective study, which included 1,266 patients with rheumatoid arthritis in primary prevention, the use of hydroxychloroquine showed a 72% reduction in the risk of cardiovascular disease and a 70% reduction in the composite endpoint of coronary heart disease, established or transient ischemic stroke.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>Furthermore, hydroxychloroquine exhibits hypolipidemic, hypoglycaemic and antithrombotic properties when administered in patients with autoimmune diseases, which can contribute significantly to reducing the risk of cardiovascular disease in these patients. At the moment, clinical evidence for hydroxychloroquine is exclusive to patients with systemic autoimmune diseases.Vaccines and other immunotherapies to mitigate atherosclerosisThe existence of both a pro-atherogenic and atheroprotective immune response has led to the hypothesis that suppression of the pro-atherogenic response or activation of the atheroprotective response could be beneficial in atherosclerosis. This suggests that immunomodulation with a vaccine or a specific antibody could favourably change the natural history of the disease. Modification of the immune response by a vaccine with atherogenesis-relevant antigen(s) can condition a specific immune response against said antigen without affecting overall immunity, with a more sustained and long-term effect.Almost 60 years ago rabbits were shown to develop smaller atherosclerotic lesions after subcutaneous injection of LDL.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Subsequently, it was confirmed that vaccination with LDL could be atheroprotective in a variety of animal species, with different preparations of native or modified LDL particles, routes of administration and type of adjuvants.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> At least 7 peptides restricted by the major histocompatibility complex II of apolipoprotein B, which contain the immunodominant epitopes of LDL particles, protect against atherosclerosis when used in vaccines: p3, p6, p101, p102, p103, p183 and p210.<a class="elsevierStyleCrossRefs" href="#bib0255">51,52</a>Other strategies derived from experimental observations include administration of IgM antibodies that recognize OxLDL-associated epitopes or phosphorylcholine from apoptotic cells, heat shock protein vaccines (HSP65), and immunization against the cholesterol ester transfer protein (CETP).<a class="elsevierStyleCrossRef" href="#bib0265">53</a>We currently have solid evidence that supports the clinical efficacy of passive immunization with monoclonal antibodies against PCSK9 to reduce circulating LDL cholesterol and cardiovascular events.<a class="elsevierStyleCrossRefs" href="#bib0270">54,55</a> Furthermore, PCSK9 as a therapeutic target is safe, since humans carrying mutations with loss of null allele function in this protein’s gene are asymptomatic and resistant to atherosclerosis. Similarly, the concept of a vaccine against PCSK9 to induce neutralizing antibodies has shown promising results in animal models and is likely to move into the clinical phase soon.<a class="elsevierStyleCrossRef" href="#bib0280">56</a>Many other antigens confer atheroprotection when tested in the vaccine formulation, and it is likely that, given the complex nature of atherosclerosis, the list may be longer (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). It is expected that the systematic analysis of atherosclerosis immunogenomics, a concept similar to that used in cancer research,<a class="elsevierStyleCrossRef" href="#bib0285">57</a> will allow the identification of new antigenic epitopes of specific atherosclerotic disorders that may condition a protective immune response.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>ConclusionSystemic inflammation plays a major role in both the onset and progression of atherogenesis. However, we do not yet have a reliable therapeutic approach to curb the persistently activated inflammatory response in atherosclerosis. We must not forget the multifactorial and progressive nature of the disease, so anti-inflammatory drugs that dampen host defence mechanisms or alter vascular homeostasis are not ideal.The retention and subsequent modification of LDL particles causes innate and adaptive immune responses, which promote inflammation in the artery wall. Interrupting this vicious circle by targeting inflammatory inducers and mediators may facilitate alternative strategies to stop atherogenesis at specific stages. In this sense, the CANTOS study provides a proof of concept and should be considered a seminal study for future anti-inflammatory therapies with greater safety and efficacy. The negative results of the CIRT study suggest that the next anti-inflammatory strategies should focus on individuals whose baseline inflammatory burden allows them to benefit, a priori, from the intervention. In this sense, the researchers of the CANTOS study proposed that the quantification of high-sensitivity CRP could be sufficient to identify candidate patients, but these conclusions may not be valid for a particular patient, while they may be true for a cohort of patients. In this regard, imaging tests to detect vascular inflammation, such as Fluorine-18 Deoxyglucose Positron Emission Tomography, may be helpful in patient selection.It must be recognized that the pharmacological modulation of inflammation in the field of cardiovascular prevention has been and is a real challenge. From the review we can point out that not all the anti-inflammatory agents tested in the clinical trials provided a cardiovascular benefit, and this increases the possibility that the anti-inflammatory pathway/mechanism chosen as a therapeutic target will be decisive in obtaining positive results. In this sense, and without wanting to be visionaries, in addition to IL-1β, IL-1α could be considered as a future anti-inflammatory therapy for atherosclerosis; or defective efferocytosis may be a potential therapeutic target to promote inflammation resolution in atherosclerosis. The idea of developing vaccination strategies to modulate atherosclerosis is both exciting and scientifically stimulating, but it is still in the early stages.Conflict of interestsThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1471566" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1340196" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1471565" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1340195" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Impact of lipid-lowering drug treatment on inflammation" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Reduction of inflammation as a therapeutic strategy in cardiovascular prevention" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Conventional anti-inflammatory drugs" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Therapies against specific inflammatory mediators" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Colchicine" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Canakinumab" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Methotrexate" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Hydroxychloroquine" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Vaccines and other immunotherapies to mitigate atherosclerosis" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-02-26" "fechaAceptado" => "2020-04-08" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1340196" "palabras" => array:5 [ 0 => "Atherosclerosis" 1 => "Cardiovascular disease" 2 => "Inflammation" 3 => "Anti-inflammatory therapy" 4 => "Vaccination" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1340195" "palabras" => array:5 [ 0 => "Aterosclerosis" 1 => "Enfermedad cardiovascular" 2 => "Inflamación" 3 => "Terapia antiinflamatoria" 4 => "Vacuna" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The recognition of atherogenesis as an active process rather than a passive cholesterol storage disease has underlined key inflammatory mechanisms. Hence, innate and adaptive immune responses play an important role in the onset and progression of atherosclerosis. More recently, some clinical studies were designed to address the impact of anti-inflammatory intervention strategies in reducing risk of cardiovascular disease beyond the management of classic risk factors. Therefore, we review first the pathophysiological contribution of inflammation to atherosclerosis and the effect of lipid-lowering drugs on inflammatory biomarkers. Next, we address the effect of classic anti-inflammatory drugs, pharmacological therapies targeting specific inflammatory mediators and vaccines in cardiovascular prevention." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El reconocimiento de la aterogénesis como un proceso dinámico en vez de un depósito pasivo de colesterol ha subrayado la existencia de mecanismos inflamatorios claves. Así, la respuesta inmune, tanto innata como adaptativa, desempeña un papel importante en el inicio y la progresión de la aterosclerosis. Más recientemente, algunos estudios clínicos han sido diseñados para abordar el impacto de las estrategias de intervención antiinflamatoria en la reducción del riesgo de enfermedad cardiovascular más allá del control de los factores clásicos de riesgo. Por todo ello, revisamos en primer lugar la contribución fisiopatológica de la inflamación en la aterosclerosis y el efecto del tratamiento farmacológico hipolipidemiante en los marcadores de inflamación. A continuación, abordamos el efecto de los fármacos antiinflamatorios clásicos, de los tratamientos farmacológicos dirigidos a mediadores inflamatorios específicos y de las vacunas en la prevención cardiovascular." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Pedro-Botet J, Climent E, Benaiges D. Arteriosclerosis e inflamación. Nuevos enfoques terapéuticos. Med Clin (Barc). 2020;155:256–262." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CV: cardiovascular; DM2: diabetes mellitus type 2; CHD: coronary heart disease; HR: hazard ratio; HF: heart failure; PCI, percutaneous coronary intervention; IL: interleukin; MI: myocardial infarction; OxLDL: oxidized low-density lipoproteins; LpPLA2: phospholipases A2 associated with lipoproteins; p38 MAPK: mitogen-activated p38 protein kinases; hsCRP: high-sensitivity C-reactive protein; ACS: acute coronary syndrome; MS, metabolic syndrome; sPLA2: segregated phospholipases A2; TNF: tumour necrosis factor." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug/Comparator \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Therapeutic target \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical follow-up \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primary endpoint \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main outcome \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ARISE<a class="elsevierStyleCrossRef" href="#bib0110">22</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,144 post-SCA (<1 year) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Succinobulol/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OxLDL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CV death/resuscitated cardiac arrest/MI/stroke/unstable angina/revascularization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 1.00; 95% CI: 0.89−1.13; p = 0.96 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VISTA-16<a class="elsevierStyleCrossRef" href="#bib0115">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,145 post-SCA (96 h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Varespladib/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">sPLA2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.1 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CV death/non-fatal MI/non-fatal stroke/unstable angina with ischemia requiring admission \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 1.25; 95% CI: 0.97−1.61; p = 0.08 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">STABILITY<a class="elsevierStyleCrossRef" href="#bib0120">24</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15,828 with stable CHD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Darapladib/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LpPLA2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.7 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CV/MI/stroke death \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 0.94; 95% CI: 0.85−1.03; p = 0.20 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SOLID-TIMI 52<a class="elsevierStyleCrossRef" href="#bib0125">25</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13,026 post-SCA (30 days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Darapladib/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LpPLA2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.5 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Coronary death/MI/revascularization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 1.00; 95% CI: 0.91−1.09; p = 0.93 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SELECT-ACS<a class="elsevierStyleCrossRef" href="#bib0130">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">544 MI without ↑ST scheduled for coronary angiography and possible PCI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inclacumab/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P-selectin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 h post-PCI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Troponin change i at baseline, 16 and 24 h after PCI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No effect in reducing myocardial damage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SELECT-CABG<a class="elsevierStyleCrossRef" href="#bib0135">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">384 postoperative coronary artery bypass surgery (4 h–6 weeks) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inclacumab/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P-selectin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 year \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Saphenous vein graft disease assessed by quantitative coronary angiography one year after coronary bypass surgery \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Failure to reduce saphenous vein graft disease after coronary artery bypass surgery \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LATITUDE-TIMI 60<a class="elsevierStyleCrossRef" href="#bib0140">28</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3,503 hospitalized for MI and ≥ 1 CV risk predictor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Losmapimod/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p38 MAPK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CV death/MI/severe recurrent ischemia requiring revascularization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 1.16; 95% CI: 0.91−1.47; p = 0.24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VCU-ART + VCU-ART2<a class="elsevierStyleCrossRef" href="#bib0145">29</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 with SCA < 24 h + ↑ST and angiography for emergency PCI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anakinra/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-1RI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Death/cardiac death/MI/stroke/unstable angina/symptomatic HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutral effect in CV episodes; long-term reduction in the risk of post-MI HF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VCU-ART3<a class="elsevierStyleCrossRef" href="#bib0150">30</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 MI with ↑ST (<12 h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anakinra/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-1RI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Assess cardiac remodelling and function and CV episodes (CV death, MI, revascularization, new-onset CI) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Under development \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LoDoCo<a class="elsevierStyleCrossRef" href="#bib0165">33</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">532 with stable CHD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colchicine/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophil motility \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ACS/out-of-hospital cardiac arrest/non-cardioembolic ischemic stroke \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 0.33; 95% CI: 0.18−0.59; p < 0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ColCot<a class="elsevierStyleCrossRef" href="#bib0170">34</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4745 post-MI (30 days) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colchicine/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophil motility \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22.6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CV death/resuscitated cardiac arrest/MI/stroke/emergency hospitalization for angina requiring revascularization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 0.77; 95% CI: 0.61−0.96; p = 0.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LoDoCo2<a class="elsevierStyleCrossRef" href="#bib0180">36</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5,522 with stable CHD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colchicine/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophil motility \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Until reaching 331 primary endpoints with ≥ 1-year follow-up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CV death/MI/Ischemic stroke/revascularization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Under development \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CANTOS<a class="elsevierStyleCrossRef" href="#bib0185">37</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10,061 post-MI with hsCRP > 2 mg/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Canakinumab/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-1β \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.7 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-fatal MI/non-fatal stroke/CV death \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 0.85; 95% CI: 0.74−0.98; p = 0.021<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a>HR 0.86; 95% CI: 0.75−0.99; p = 0.031<a class="elsevierStyleCrossRef" href="#tblfn0010">**</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CIRT<a class="elsevierStyleCrossRef" href="#bib0230">46</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4,786 with MI or multivessel CHD and DM2 or MS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate/placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I L-6, TNF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trial discontinued at 2.3 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-fatal MI/non-fatal stroke/CV death/unstable angina with revascularization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HR 0.96; 95% CI: 0.79−1.16; p = 0.67 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2532273.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "For the subcutaneous dose of 150 mg/3 months." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "**" "nota" => "For the subcutaneous dose of 300 mg/3 months." ] ] ] "descripcion" => array:1 [ "en" => "Main clinical studies with anti-inflammatory pharmacological intervention in patients with cardiovascular disease." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Lipid-related antigens \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-lipid related antigens \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low-density lipoproteins (native or modified) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chlamydia and Streptococcus pneumoniae \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apolipoprotein B-100-derived peptides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thermal shock protein 60 and 65 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phosphorylcholine primary group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Variable beta T-cell receptor 31-derived peptide \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cholesterol ester transfer protein \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CD99 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apolipoprotein E-derived peptide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C5a receiver \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proprotein convertase subtilisin/kexin 9 peptides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interleukins \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vascular endothelial growth factor receptor 2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">B2-glycoprotein 1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fibronectin \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2532272.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Antigens used in the development of vaccines against atherosclerosis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:57 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.C. 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Atherosclerosis and inflammation. New therapeutic approaches

Arteriosclerosis e inflamación. Nuevos enfoques terapéuticos

Juan Pedro-Botet

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86620@parcdesalutmar.cat

Corresponding author.

, Elisenda Climent, David Benaiges

Unidad de Lípidos y Riesgo Vascular, Servicio de Endocrinología y Nutrición, Hospital del Mar, Universidad Autónoma de Barcelona, Barcelona, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Atherosclerosis is a disease that has affected humans for millennia&#44; as evidenced by the degenerative changes found in the arterial tree of 47 out of 137 mummies from 4 different geographic areas &#40;Egypt&#44; Peru&#44; the ancestral peoples of southwestern America and the Unangan from the Aleutian Islands&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> vascular lesions that do not differ from those currently observed&#46; On the other hand&#44; evidence from experimental and human models of atherosclerosis&#44; from biomarker studies and more recently from clinical intervention trials has provided over time further clarification of the mechanisms involved in atherogenesis&#46; So&#44; in the <span class="elsevierStyleSmallCaps">XIX</span> century&#44; German pathologist Rudolf Virchow<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> already recognized the inflammatory nature of atherosclerosis&#58; &#8220;&#8230; Inflammation of the arterial inner layer is the starting point of the so-called atheromatous degeneration&#8230;&#8221;&#46; Unfortunately&#44; for more than a century this theory gave way to the view of atheroma as a passive deposit of lipids&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">It is now well known that atherosclerosis is a chronic low-grade inflammatory disease that occurs in the artery wall and is initiated primarily in response to endogenously modified elements&#44; especially oxidized low-density lipoproteins &#40;OxLDL&#41;&#44; which stimulate innate and adaptive immune responses&#46; Intracellular cholesterol accumulation is the trigger for the inflammasome response leading to the production of inflammatory mediators such as interleukin &#40;IL&#41;-1&#946;&#46; The innate response begins with the activation of endothelial cells in the arterial wall and monocytes&#47;macrophages&#59; the adaptive immune response then occurs to a series of potential antigens presented to effector T lymphocytes by antigen presenting cells&#44; such as dendritic cells&#46; Both innate and adaptive immune responses are key in the onset and development of atherosclerosis&#46; It should be said that the cellular and molecular interactions in atherogenesis do not differ from those that occur in chronic inflammatory diseases such as rheumatoid arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Almost all immunoinflammatory system cell types&#44; as well as many pro and anti-inflammatory cytokines and chemokines&#44; have also been identified in atherosclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A process called efferocytosis&#44; or the efficient clearance of apoptotic cells by phagocytes&#44; ensures resolution of inflammatory responses&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> This involves the recognition of certain signals&#44; such as the exposure of phosphatidylserine in apoptotic cells to their respective macrophage receptors&#44; as well as to bridging molecules that mediate binding&#46; Opposite signals for non-phagocytosis&#44; such as CD47 expression&#44; also play a role and influence atherogenesis&#46; Apoptotic cell uptake is associated with increased expression of anti-inflammatory cytokines &#40;transforming growth factor-&#946; and IL-10&#41;&#44; as well as a decrease in the expression of proinflammatory cytokines &#40;IL-8 and IL-1&#946;&#41; by macrophages&#46; Thus&#44; efficient efferocytosis protects from atherogenesis by removing cellular debris and creating an anti-inflammatory medium&#46; Furthermore&#44; the uptake of cellular debris favours the production of lipid mediators&#44; such as lipoxins&#44; resolvins and maresins&#44; which actively participate in the resolution of inflammatory processes&#46; In chronic inflammation&#44; the proinflammatory environment disrupts the expression of molecules that regulate efferocytosis&#44; so that OxLDL particles compete for uptake by macrophages in atherosclerotic lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> As a result&#44; the efferocytosis becomes defective and the resolution of the inflammation&#44; driven primarily by the modified LDL particles&#44; deteriorates&#46; Under these conditions&#44; apoptotic cells accumulate with the consequent secondary necrosis and release of molecules&#44; which together have been called damage-associated molecular patterns or warning signs that further spread inflammation&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A considerable number of acute phase proteins have been recognized during inflammatory processes&#44; with C-reactive protein &#40;CRP&#41; being the most useful serum marker&#44; despite its low specificity for any particular inflammatory process&#44; including atherosclerosis&#46; High sensitivity CRP determination was developed to detect very low levels of this protein and to allow a more accurate measurement of chronic inflammation compared to standard CRP&#46; The association between high-sensitivity plasma CRP levels and the risk of cardiovascular events is debated&#44; as there is clinical evidence in favour and against&#46; Finally&#44; large cohort genetic studies have not confirmed that chronically elevated high-sensitivity CRP increases the risk of vascular events&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Despite the above&#44; some clinical practice guidelines have suggested the inclusion of high-sensitivity CRP alongside traditional vascular risk factors to improve prognostic information&#44; especially in patients with intermediate cardiovascular risk&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Impact of lipid-lowering drug treatment on inflammation</span><p id="par0025" class="elsevierStylePara elsevierViewall">Statins&#44; in addition to inhibiting HMG-CoA reductase&#44; an enzyme that limits intracellular cholesterol synthesis&#44; decrease CRP secretion by hepatocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and in certain forums it has been pointed out that the benefits of statin therapy are related to the reduction of cholesterol levels and inflammation&#46; The study <span class="elsevierStyleItalic">Justification for the Use of Statins in Prevention&#58; An Intervention Trial Evaluating Rosuvastatin</span> &#40;JUPITER&#41;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> in subjects in primary prevention with a concentration of LDL cholesterol&#8239;&#60;&#8239;130&#8239;mg&#47;dl &#40;3&#46;4&#8239;mmol&#47;l&#41; and chronically elevated CRP &#40;&#62;2&#8239;mg&#47;l&#41; showed that statin treatment significantly reduced the occurrence of cardiovascular events&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In addition to improving the lipid profile&#44; two new lipid-lowering drugs&#44; bempedoic acid and pemafibrate&#44; decrease the plasma concentration of high-sensitivity CRP to the same extent as statins&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> The first is a new oral molecule&#44; a prodrug that requires activation of the long-chain acyl-coA synthetase 1 enzyme&#44; which is present in the liver but absent in other tissues&#44; which reduces LDL cholesterol by inhibiting ATP-citrate lyase&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Pemafibrate is a new selective modulator of peroxisomal proliferator-activated receptors &#40;PPAR-&#945;&#41; which effectively lowers triglyceride levels and increases HDL cholesterol levels more significantly than fenofibrate&#44; with greater liver and kidney safety&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Other blood cholesterol lowering drugs&#44; such as ezetimibe and proprotein convertase subtilisin&#47;kexin 9 &#40;PCSK9&#41; inhibitors&#44; lead to additional significant reductions in cardiovascular events when co-administered with statins&#44; but without modifying plasma concentrations of high-sensitivity CRP&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Reduction of inflammation as a therapeutic strategy in cardiovascular prevention</span><p id="par0040" class="elsevierStylePara elsevierViewall">The lipid theory initially postulated by N&#46; Anichkov&#44; a pathologist at the Military Medical Academy in St&#46; Petersburg has provided the traditional approach to understanding atherosclerosis&#46; LDL cholesterol is undoubtedly a causal factor of atherosclerosis<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and has become the main therapeutic objective of cardiovascular prevention&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> However&#44; despite currently effective drugs&#44; such as statins&#44; ezetimibe&#44; and PCSK9 inhibitors&#44; used alone or as combination therapy&#44; we still face an unacceptably high rate of cardiovascular events&#46; Therefore&#44; once atherosclerosis is recognized and accepted as a chronic inflammation of the arterial wall&#44; it is easy to understand that anti-inflammatory strategies have emerged for the prevention of atherosclerosis complications&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conventional anti-inflammatory drugs</span><p id="par0045" class="elsevierStylePara elsevierViewall">Anti-inflammatory drugs&#44; such as glucocorticoids&#44; non-steroidal anti-inflammatory drugs&#44; and cyclooxygenase &#40;COX&#41;-2 inhibitors&#44; are highly effective in specific situations&#44; such as acute inflammation or symptomatic flares of autoimmune diseases&#46; In this clinical context&#44; the adverse reactions of these drugs are minimal due to short-term use&#44; or even accepted due to the high benefit&#47;risk ratio in symptomatic diseases&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In a population-based case-control study analysing the effects of glucocorticoids in more than 100&#44;000 patients with chronic inflammatory diseases&#44; an increase in cardiovascular events was found in those treated&#44; regardless of timing and steroids dose &#40;single or cumulative&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This may be due in part to the negative impact of glucocorticoids on cardiovascular risk factors&#44; with the usual changes in the lipid profile&#44; poor control of blood pressure&#44; weight gain&#44; and insulin resistance&#46; Apart from these harmful effects&#44; the administration of prednisolone encapsulated in lysosomal nanoparticles&#44; as an anti-inflammatory drug directed against atheroma plaque&#44; has been found to exacerbate atherosclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Selective COX-2 inhibitors are highly effective in reducing arthritic pain&#46; However&#44; the cardiovascular alert detected with rofecoxib<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> led to a re-evaluation of this therapeutic class&#46; A non-significant increase in cardiovascular risk was found with ibuprofen and diclofenac compared to naproxen&#44;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and later&#44; the <span class="elsevierStyleItalic">Prospective Randomized Evaluation of Celecoxib Integrated Safety</span> versus <span class="elsevierStyleItalic">Ibuprofen or Naproxen</span> &#40;PRECISION&#41; study in more than 27&#44;000 subjects with arthritis concluded that celecoxib&#44; at moderate doses&#44; was not inferior to ibuprofen or naproxen in cardiovascular safety&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In a sub-analysis focusing on high-risk cardiovascular patients followed for a composite of severe cardiovascular&#44; gastric&#44; and renal events&#44; as well as non-cardiac death&#44; celecoxib showed a more favourable safety profile than naproxen or ibuprofen when administered without aspirin&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Therapies against specific inflammatory mediators</span><p id="par0060" class="elsevierStylePara elsevierViewall">As a result of the large number of inflammatory mediators involved in atherogenesis&#44; multiple pathways have been identified as potential targets for cardiovascular prevention&#46; Globally&#44; most clinical trials directed against specific targets&#44; such as OxLDL particles&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> the segregated phospholipases A2 and associated with lipoproteins &#40;sPLA2 and LpPLA2&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;25</span></a> selectin P&#44;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> mitogen-activated protein kinases p38<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and even the IL-1&#946; anakinra inhibitor<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> have not been able to demonstrate cardiovascular benefits &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Colchicine</span><p id="par0065" class="elsevierStylePara elsevierViewall">Colchicine&#44; derived from the plant <span class="elsevierStyleItalic">Colchicum autumnale</span> &#40;&#8220;meadow saffron&#8221;&#41;&#44; is another drug widely used in the treatment of inflammatory conditions&#46; Thus&#44; for example&#44; it has become the conventional treatment for acute pericarditis&#44; by avoiding the rebound phenomenon of glucocorticoids&#46; Colchicine has anti-inflammatory properties as it promotes microtubule disruption&#44; inhibiting neutrophil chemotaxis&#44; impairing the functionality of the inflammasome&#44; and blocking cytokine production&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> In a cohort study&#44; its use in gout patients was associated with a 49&#37; reduction in cardiovascular events and 73&#37; reduction in all-cause mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The study <span class="elsevierStyleItalic">Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease</span> &#40;LoDoCo&#41;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> pioneered the use of colchicine in the secondary prevention of cardiovascular disease&#46; This open-label&#44; placebo-controlled trial which randomized 532 patients with stable coronary heart disease to colchicine 0&#46;5&#8239;mg&#47;day versus control&#44; showed a highly significant reduction in the rate of cardiovascular events during a 3-year follow-up&#46; More recently&#44; clear signs of stabilization of the atheroma plaque was observed by coronary computed tomography in patients with acute coronary syndrome treated with colchicine 0&#46;5&#8239;mg&#47;day at one year of follow-up&#46; This was attributed to the anti-inflammatory properties of colchicine&#44; as demonstrated by the reductions in the CRP&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> These promising results have generated 4 large-scale investigations to confirm the possible cardiovascular benefits of colchicine&#46; Among these&#44; the <span class="elsevierStyleItalic">Colchicine Cardiovascular Outcomes Trial</span> &#40;COLCOT&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> designed to assess the cardiovascular effects of colchicine at doses of 0&#46;5&#8239;mg&#47;day in 4&#44;745 patients with a recent myocardial infarction&#44; demonstrated a reduction in the composite primary endpoint consisting of cardiovascular death&#44; resuscitated cardiac arrest&#44; myocardial infarction&#44; stroke&#44; or emergency hospitalization for angina leading to 23&#37; coronary revascularization&#46; This study recorded a significant increase in the number of pneumonia cases in the active treatment arm&#46; In general&#44; at the usual doses&#44; colchicine causes gastrointestinal side effects that cause discontinuation of the medication in more than 10&#37; of patients&#46; The LoDoCo2<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> &#40;Registry number&#58; ACTRN 12614000093684&#41;&#44; a randomized controlled trial evaluating the effect of low-dose colchicine in patients with stable ischemic heart disease&#44; has already recruited more than 4&#44;000 patients&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Canakinumab</span><p id="par0070" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Canakinumab Antiinflammatory Thrombosis Outcome Study</span> &#40;CANTOS&#41;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> tested a specific anti-inflammatory treatment&#44; a human monoclonal antibody that inhibits IL-1&#946;&#44; at doses of 50&#44; 150 and 300&#8239;mg&#46; In patients with prior myocardial infarction&#44; under optimal medical treatment and chronic high levels of high-sensitivity CRP&#44; canakinumab decreased the concentration of high-sensitivity CRP and the rate of cardiovascular events compared to placebo in a dose-dependent manner&#44; regardless of lipid profile&#46; The researchers pre-specified 2 complementary analyses&#59; in the first&#44; they showed a significant decrease in cancer mortality in the canakinumab group&#44; with a lower incidence of lung cancer at doses of 150 and 300&#8239;mg&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In a second analysis&#44; they determined which subgroup of patients benefited the most from treatment with canakinumab&#44; based on the degree of reduction in high-sensitivity CRP&#46; In this sense&#44; reaching a high-sensitivity CRP&#8239;&#60;&#8239;2&#8239;mg&#47;l was associated with a 31&#37; reduction in cardiovascular and all-cause mortality compared to the placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Lately&#44; 2 more subanalyses of the CANTOS study have been published&#46; None of the canakinumab doses used was accompanied by an increase in new-onset diabetes or a worsening of the levels of glycated hemoglobin&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> The other analysis compared 1&#44;872 patients with glomerular filtration&#8239;&#60;&#8239;60&#8239;ml&#47;min&#47;1&#46;73&#8239;m<span class="elsevierStyleSup">2</span> with the remaining &#8764;8&#44;000 patients included in CANTOS&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Canakinumab reduced the number of serious cardiovascular events in patients with chronic kidney disease&#44; and was particularly effective in those who achieved high-sensitivity CRP&#8239;&#60;&#8239;2&#8239;mg&#47;l after the first dose of the drug&#59; in these there was a decrease in the number of cardiovascular episodes&#44; as well as cardiovascular and all-cause mortality&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The CANTOS study was the first to highlight the positive correlation between high-sensitivity CRP and cardiovascular events&#44; where the lower levels of high-sensitivity CRP achieved were related to a lower risk of future cardiovascular events&#46; However&#44; some aspects of the study deserve additional comment&#46; The reduction in cardiovascular risk in absolute terms was modest &#40;0&#46;64 per 100 person-years&#41;&#59; there was a small&#44; but relevant&#44; risk of serious and fatal infections in the Canakinumab group&#44; and the estimated cost of treatment was about &#36;200&#44;000 a year&#46; It should also be stressed that canakinumab treatment has not been tested against statins combined with ezetimibe and&#47;or PCSK9 inhibitors&#44; so the question of residual vascular risk in patients with elevated high-sensitivity PCR and very low LDL cholesterol concentrations and&#44; ultimately&#44; whether treatment with an anti-IL-1&#946; monoclonal antibody would be beneficial in these cases&#44; remains open&#46; Furthermore&#44; all currently recommended lipid-lowering drugs&#44; including PCSK9 inhibitors&#44; have demonstrated beneficial effects on the composition and regression of the atheromatous plaque&#44; results not available for treatment with canakinumab&#46; This undoubtedly led the <span class="elsevierStyleItalic">Food and Drug Administration</span> to decline the approval of canakinumab for cardiovascular risk reduction based on the data from the CANTOS study&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In addition to IL-1&#946;&#44; its sister isoform&#44; IL-1&#945;&#44; exercises many of the same actions&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> but with considerably different cell biology and biochemistry&#46; In this sense&#44; IL-1&#945; does not require inflammasome activation in order to exercise its biological activity&#44; it signals through contact or acts at noticeably short distances&#44; since it is mainly associated with cell surface&#46; Experimental evidence supports the causal role of IL-1&#945; in experimental atherosclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> and an antibody &#40;xilonix&#41; that neutralizes the human IL-1&#945; is available for clinical use&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Methotrexate</span><p id="par0085" class="elsevierStylePara elsevierViewall">Folic acid antagonist methotrexate blocks the synthesis of purines and pyrimidines by inhibiting key enzymes such as dihydrofolate reductase and thymidylate synthetase&#46; In addition&#44; it reduces the proliferation of antigen-dependent T cells and inhibits adenosine deaminase and adenosine monophosphate deaminase&#44; with the consequent release of adenosine&#44; a molecule with anti-inflammatory properties&#46; At the same time&#44; it seems to have antiatherogenic properties&#44; attributed to the activation of the adenosine A2A receptor&#44; which leads to an improvement in reverse cholesterol transport and a decrease in the formation of foamy cells by THP-1 macrophages&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Observational studies of patients with rheumatoid arthritis and psoriatic arthritis receiving low-dose methotrexate had reported fewer cardiovascular events than those receiving other therapies or placebo&#46; For this reason&#44; methotrexate was tested as an anti-inflammatory strategy in the <span class="elsevierStyleItalic">Cardiovascular Inflammation Reduction Trial</span> &#40;CIRT&#41;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> carried out in collaboration with the <span class="elsevierStyleItalic">National Heart&#44; Lung&#44; and Blood Institute</span> and designed in parallel to the CANTOS studio&#46; Very low doses of methotrexate were assigned &#40;10&#8239;mg&#47;week&#41; versus placebo in 7&#44;000 patients with stable ischemic heart disease&#46; The study was discontinued due to lack of efficacy after a 2&#46;3-year follow-up&#46; At that dose and in a non-rheumatological population&#44; methotrexate had no effect on IL-6 concentrations or high-sensitivity CRP&#44; which could explain the neutral results of the trial&#46; Also&#44; the baseline level of inflammation in the CRIT study population was in a low-risk area &#40;high-sensitivity CRP 1&#46;6&#8239;mg&#47;l&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Hydroxychloroquine</span><p id="par0095" class="elsevierStylePara elsevierViewall">Hydroxychloroquine is used in the treatment of certain autoimmune diseases&#44; such as rheumatoid arthritis and systemic lupus erythematosus&#44; as well as in the prevention and treatment of certain types of malaria&#46; It exerts its immunomodulatory properties through inflammatory pathway suppression by preventing activation of the <span class="elsevierStyleItalic">Toll</span>-type receptor&#44; which is necessary for expression of interferon-regulated genes and for production of TNF-&#945;&#44; a major component of the cell-mediated inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">High-dose hydroxychloroquine therapy &#40;400&#8239;mg&#47;day&#41; has been independently associated with a 56&#46;8&#37; reduction in the risk of cardiovascular morbidity in patients with rheumatoid arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> In a retrospective study&#44; which included 1&#44;266 patients with rheumatoid arthritis in primary prevention&#44; the use of hydroxychloroquine showed a 72&#37; reduction in the risk of cardiovascular disease and a 70&#37; reduction in the composite endpoint of coronary heart disease&#44; established or transient ischemic stroke&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Furthermore&#44; hydroxychloroquine exhibits hypolipidemic&#44; hypoglycaemic and antithrombotic properties when administered in patients with autoimmune diseases&#44; which can contribute significantly to reducing the risk of cardiovascular disease in these patients&#46; At the moment&#44; clinical evidence for hydroxychloroquine is exclusive to patients with systemic autoimmune diseases&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Vaccines and other immunotherapies to mitigate atherosclerosis</span><p id="par0110" class="elsevierStylePara elsevierViewall">The existence of both a pro-atherogenic and atheroprotective immune response has led to the hypothesis that suppression of the pro-atherogenic response or activation of the atheroprotective response could be beneficial in atherosclerosis&#46; This suggests that immunomodulation with a vaccine or a specific antibody could favourably change the natural history of the disease&#46; Modification of the immune response by a vaccine with atherogenesis-relevant antigen&#40;s&#41; can condition a specific immune response against said antigen without affecting overall immunity&#44; with a more sustained and long-term effect&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Almost 60 years ago rabbits were shown to develop smaller atherosclerotic lesions after subcutaneous injection of LDL&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Subsequently&#44; it was confirmed that vaccination with LDL could be atheroprotective in a variety of animal species&#44; with different preparations of native or modified LDL particles&#44; routes of administration and type of adjuvants&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> At least 7 peptides restricted by the major histocompatibility complex <span class="elsevierStyleSmallCaps">II</span> of apolipoprotein B&#44; which contain the immunodominant epitopes of LDL particles&#44; protect against atherosclerosis when used in vaccines&#58; p3&#44; p6&#44; p101&#44; p102&#44; p103&#44; p183 and p210&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;52</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Other strategies derived from experimental observations include administration of IgM antibodies that recognize OxLDL-associated epitopes or phosphorylcholine from apoptotic cells&#44; heat shock protein vaccines &#40;HSP65&#41;&#44; and immunization against the cholesterol ester transfer protein &#40;CETP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">We currently have solid evidence that supports the clinical efficacy of passive immunization with monoclonal antibodies against PCSK9 to reduce circulating LDL cholesterol and cardiovascular events&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;55</span></a> Furthermore&#44; PCSK9 as a therapeutic target is safe&#44; since humans carrying mutations with loss of null allele function in this protein&#8217;s gene are asymptomatic and resistant to atherosclerosis&#46; Similarly&#44; the concept of a vaccine against PCSK9 to induce neutralizing antibodies has shown promising results in animal models and is likely to move into the clinical phase soon&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Many other antigens confer atheroprotection when tested in the vaccine formulation&#44; and it is likely that&#44; given the complex nature of atherosclerosis&#44; the list may be longer &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; It is expected that the systematic analysis of atherosclerosis immunogenomics&#44; a concept similar to that used in cancer research&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> will allow the identification of new antigenic epitopes of specific atherosclerotic disorders that may condition a protective immune response&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusion</span><p id="par0135" class="elsevierStylePara elsevierViewall">Systemic inflammation plays a major role in both the onset and progression of atherogenesis&#46; However&#44; we do not yet have a reliable therapeutic approach to curb the persistently activated inflammatory response in atherosclerosis&#46; We must not forget the multifactorial and progressive nature of the disease&#44; so anti-inflammatory drugs that dampen host defence mechanisms or alter vascular homeostasis are not ideal&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The retention and subsequent modification of LDL particles causes innate and adaptive immune responses&#44; which promote inflammation in the artery wall&#46; Interrupting this vicious circle by targeting inflammatory inducers and mediators may facilitate alternative strategies to stop atherogenesis at specific stages&#46; In this sense&#44; the CANTOS study provides a proof of concept and should be considered a seminal study for future anti-inflammatory therapies with greater safety and efficacy&#46; The negative results of the CIRT study suggest that the next anti-inflammatory strategies should focus on individuals whose baseline inflammatory burden allows them to benefit&#44; <span class="elsevierStyleItalic">a priori</span>&#44; from the intervention&#46; In this sense&#44; the researchers of the CANTOS study proposed that the quantification of high-sensitivity CRP could be sufficient to identify candidate patients&#44; but these conclusions may not be valid for a particular patient&#44; while they may be true for a cohort of patients&#46; In this regard&#44; imaging tests to detect vascular inflammation&#44; such as Fluorine-18 Deoxyglucose Positron Emission Tomography&#44; may be helpful in patient selection&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">It must be recognized that the pharmacological modulation of inflammation in the field of cardiovascular prevention has been and is a real challenge&#46; From the review we can point out that not all the anti-inflammatory agents tested in the clinical trials provided a cardiovascular benefit&#44; and this increases the possibility that the anti-inflammatory pathway&#47;mechanism chosen as a therapeutic target will be decisive in obtaining positive results&#46; In this sense&#44; and without wanting to be visionaries&#44; in addition to IL-1&#946;&#44; IL-1&#945; could be considered as a future anti-inflammatory therapy for atherosclerosis&#59; or defective efferocytosis may be a potential therapeutic target to promote inflammation resolution in atherosclerosis&#46; The idea of developing vaccination strategies to modulate atherosclerosis is both exciting and scientifically stimulating&#44; but it is still in the early stages&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of interests</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Impact of lipid-lowering drug treatment on inflammation"
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          "titulo" => "Reduction of inflammation as a therapeutic strategy in cardiovascular prevention"
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              "titulo" => "Conventional anti-inflammatory drugs"
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              "identificador" => "sec0025"
              "titulo" => "Therapies against specific inflammatory mediators"
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            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Colchicine"
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              "identificador" => "sec0035"
              "titulo" => "Canakinumab"
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              "titulo" => "Methotrexate"
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              "titulo" => "Hydroxychloroquine"
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          "titulo" => "Vaccines and other immunotherapies to mitigate atherosclerosis"
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          "titulo" => "Conclusion"
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    "fechaAceptado" => "2020-04-08"
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            0 => "Atherosclerosis"
            1 => "Cardiovascular disease"
            2 => "Inflammation"
            3 => "Anti-inflammatory therapy"
            4 => "Vaccination"
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            0 => "Aterosclerosis"
            1 => "Enfermedad cardiovascular"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The recognition of atherogenesis as an active process rather than a passive cholesterol storage disease has underlined key inflammatory mechanisms&#46; Hence&#44; innate and adaptive immune responses play an important role in the onset and progression of atherosclerosis&#46; More recently&#44; some clinical studies were designed to address the impact of anti-inflammatory intervention strategies in reducing risk of cardiovascular disease beyond the management of classic risk factors&#46; Therefore&#44; we review first the pathophysiological contribution of inflammation to atherosclerosis and the effect of lipid-lowering drugs on inflammatory biomarkers&#46; Next&#44; we address the effect of classic anti-inflammatory drugs&#44; pharmacological therapies targeting specific inflammatory mediators and vaccines in cardiovascular prevention&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El reconocimiento de la aterog&#233;nesis como un proceso din&#225;mico en vez de un dep&#243;sito pasivo de colesterol ha subrayado la existencia de mecanismos inflamatorios claves&#46; As&#237;&#44; la respuesta inmune&#44; tanto innata como adaptativa&#44; desempe&#241;a un papel importante en el inicio y la progresi&#243;n de la aterosclerosis&#46; M&#225;s recientemente&#44; algunos estudios cl&#237;nicos han sido dise&#241;ados para abordar el impacto de las estrategias de intervenci&#243;n antiinflamatoria en la reducci&#243;n del riesgo de enfermedad cardiovascular m&#225;s all&#225; del control de los factores cl&#225;sicos de riesgo&#46; Por todo ello&#44; revisamos en primer lugar la contribuci&#243;n fisiopatol&#243;gica de la inflamaci&#243;n en la aterosclerosis y el efecto del tratamiento farmacol&#243;gico hipolipidemiante en los marcadores de inflamaci&#243;n&#46; A continuaci&#243;n&#44; abordamos el efecto de los f&#225;rmacos antiinflamatorios cl&#225;sicos&#44; de los tratamientos farmacol&#243;gicos dirigidos a mediadores inflamatorios espec&#237;ficos y de las vacunas en la prevenci&#243;n cardiovascular&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Pedro-Botet J&#44; Climent E&#44; Benaiges D&#46; Arteriosclerosis e inflamaci&#243;n&#46; Nuevos enfoques terap&#233;uticos&#46; Med Clin &#40;Barc&#41;&#46; 2020&#59;155&#58;256&#8211;262&#46;</p>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">CV&#58; cardiovascular&#59; DM2&#58; diabetes mellitus type 2&#59; CHD&#58; coronary heart disease&#59; HR&#58; <span class="elsevierStyleItalic">hazard ratio</span>&#59; HF&#58; heart failure&#59; PCI&#44; percutaneous coronary intervention&#59; IL&#58; interleukin&#59; MI&#58; myocardial infarction&#59; OxLDL&#58; oxidized low-density lipoproteins&#59; LpPLA<span class="elsevierStyleInf">2</span>&#58; phospholipases A<span class="elsevierStyleInf">2</span> associated with lipoproteins&#59; p38 MAPK&#58; mitogen-activated p38 protein kinases&#59; hsCRP&#58; high-sensitivity C-reactive protein&#59; ACS&#58; acute coronary syndrome&#59; MS&#44; metabolic syndrome&#59; sPLA<span class="elsevierStyleInf">2</span>&#58; segregated phospholipases A<span class="elsevierStyleInf">2</span>&#59; TNF&#58; tumour necrosis factor&#46;</p>"
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ARISE<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#44;144 post-SCA &#40;&#60;1&#8239;year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Succinobulol&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OxLDL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV death&#47;resuscitated cardiac arrest&#47;MI&#47;stroke&#47;unstable angina&#47;revascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 1&#46;00&#59; 95&#37; CI&#58; 0&#46;89&#8722;1&#46;13&#59; p&#8239;&#61;&#8239;0&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VISTA-16<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44;145 post-SCA &#40;96&#8239;h&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Varespladib&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">sPLA<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;1 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV death&#47;non-fatal MI&#47;non-fatal stroke&#47;unstable angina with ischemia requiring admission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 1&#46;25&#59; 95&#37; CI&#58; 0&#46;97&#8722;1&#46;61&#59; p&#8239;&#61;&#8239;0&#46;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">STABILITY<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#44;828 with stable CHD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Darapladib&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LpPLA<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;7 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV&#47;MI&#47;stroke death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 0&#46;94&#59; 95&#37; CI&#58; 0&#46;85&#8722;1&#46;03&#59; p&#8239;&#61;&#8239;0&#46;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SOLID-TIMI 52<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#44;026 post-SCA &#40;30 days&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Darapladib&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LpPLA<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;5 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Coronary death&#47;MI&#47;revascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 1&#46;00&#59; 95&#37; CI&#58; 0&#46;91&#8722;1&#46;09&#59; p&#8239;&#61;&#8239;0&#46;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SELECT-ACS<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">544 MI without &#8593;ST scheduled for coronary angiography and possible PCI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inclacumab&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P-selectin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#8239;h post-PCI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Troponin change <span class="elsevierStyleSmallCaps">i</span> at baseline&#44; 16 and 24&#8239;h after PCI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No effect in reducing myocardial damage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SELECT-CABG<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">384 postoperative coronary artery bypass surgery &#40;4&#8239;h&#8211;6 weeks&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inclacumab&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P-selectin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Saphenous vein graft disease assessed by quantitative coronary angiography one year after coronary bypass surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Failure to reduce saphenous vein graft disease after coronary artery bypass surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LATITUDE-TIMI 60<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#44;503 hospitalized for MI and&#8239;&#8805;&#8239;1 CV risk predictor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Losmapimod&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p38 MAPK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV death&#47;MI&#47;severe recurrent ischemia requiring revascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 1&#46;16&#59; 95&#37; CI&#58; 0&#46;91&#8722;1&#46;47&#59; p&#8239;&#61;&#8239;0&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VCU-ART&#8239;&#43;&#8239;VCU-ART2<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 with SCA&#8239;&#60;&#8239;24&#8239;h&#8239;&#43;&#8239;&#8593;ST and angiography for emergency PCI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anakinra&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-1RI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Death&#47;cardiac death&#47;MI&#47;stroke&#47;unstable angina&#47;symptomatic HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutral effect in CV episodes&#59; long-term reduction in the risk of post-MI HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VCU-ART3<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#8239;MI with &#8593;ST &#40;&#60;12&#8239;h&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anakinra&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-1RI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Assess cardiac remodelling and function and CV episodes &#40;CV death&#44; MI&#44; revascularization&#44; new-onset CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Under development&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LoDoCo<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">532 with stable CHD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colchicine&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutrophil motility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ACS&#47;out-of-hospital cardiac arrest&#47;non-cardioembolic ischemic stroke&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 0&#46;33&#59; 95&#37; CI&#58; 0&#46;18&#8722;0&#46;59&#59; p&#8239;&#60;&#8239;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ColCot<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4745 post-MI &#40;30 days&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colchicine&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutrophil motility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#46;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV death&#47;resuscitated cardiac arrest&#47;MI&#47;stroke&#47;emergency hospitalization for angina requiring revascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 0&#46;77&#59; 95&#37; CI&#58; 0&#46;61&#8722;0&#46;96&#59; p&#8239;&#61;&#8239;0&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LoDoCo2<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44;522 with stable CHD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colchicine&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutrophil motility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Until reaching 331 primary endpoints with&#8239;&#8805;&#8239;1-year follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CV death&#47;MI&#47;Ischemic stroke&#47;revascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Under development&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CANTOS<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44;061 post-MI with hsCRP&#8239;&#62;&#8239;2&#8239;mg&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Canakinumab&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-1&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;7 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-fatal MI&#47;non-fatal stroke&#47;CV death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 0&#46;85&#59; 95&#37; CI&#58; 0&#46;74&#8722;0&#46;98&#59; p&#8239;&#61;&#8239;0&#46;021<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>HR 0&#46;86&#59; 95&#37; CI&#58; 0&#46;75&#8722;0&#46;99&#59; p&#8239;&#61;&#8239;0&#46;031<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CIRT<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44;786 with MI or multivessel CHD and DM2 or MS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&#47;placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I L-6&#44; TNF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trial discontinued at 2&#46;3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-fatal MI&#47;non-fatal stroke&#47;CV death&#47;unstable angina with revascularization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HR 0&#46;96&#59; 95&#37; CI&#58; 0&#46;79&#8722;1&#46;16&#59; p&#8239;&#61;&#8239;0&#46;67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">For the subcutaneous dose of 300&#8239;mg&#47;3 months&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Main clinical studies with anti-inflammatory pharmacological intervention in patients with cardiovascular disease&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Lipid-related antigens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-lipid related antigens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low-density lipoproteins &#40;native or modified&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Chlamydia and Streptococcus pneumoniae</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Apolipoprotein B-100-derived peptides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thermal shock protein 60 and 65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phosphorylcholine primary group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variable beta T-cell receptor 31-derived peptide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cholesterol ester transfer protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Apolipoprotein E-derived peptide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C5a receiver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Proprotein convertase subtilisin&#47;kexin 9 peptides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interleukins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vascular endothelial growth factor receptor 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B2-glycoprotein 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibronectin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Antigens used in the development of vaccines against atherosclerosis&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:57 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Atherosclerosis across 4000 years of human history&#58; the Horus study of four ancient populations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;C&#46; Thompson"
                            1 => "A&#46;H&#46; Allam"
                            2 => "G&#46;P&#46; Lombardi"
                            3 => "L&#46;S&#46; Wann"
                            4 => "M&#46;L&#46; Sutherland"
                            5 => "J&#46;D&#46; Sutherland"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(13)60598-X"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2013"
                        "volumen" => "381"
                        "paginaInicial" => "1211"
                        "paginaFinal" => "1222"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23489753"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cellular pathology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46; Virchow"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:3 [
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