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"documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Med Clin. 2015;145:62-6" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 16 "formatos" => array:2 [ "HTML" => 13 "PDF" => 3 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief report</span>" "titulo" => "Usefulness of <span class="elsevierStyleSup">18</span>FDG PET-CT scan as a diagnostic tool of fever of unknown origin" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "62" "paginaFinal" => "66" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad de la tomografía por emisión de positrones con <span class="elsevierStyleSup">18</span>F-Fluorodesoxiglucosa combinada con tomografía computarizada en la orientación diagnóstica de la fiebre de origen desconocido" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1340 "Ancho" => 1400 "Tamanyo" => 185544 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Female patient aged 66, in the study with positron emission tomography combined with computed tomography following administration of 222<span class="elsevierStyleHsp" style=""></span>MBq of fluorodeoxyglucose marked by fluoride 18 (<span class="elsevierStyleSup">18</span>F-FDG) due to fever of an unknown origin. The <span class="elsevierStyleSup">18</span>F-FDG showed pathological deposits in the arterial wall of the thoracic aorta (continuous arrow) and abdominal aorta (discontinued arrow), and also in the left rib cage (arrow head) relating to post-traumatic rib fractures which the patient had mentioned. Lab findings demonstrated elevated reactive protein C levels (31.3<span class="elsevierStyleHsp" style=""></span>mg/l). Final diagnosis was giant cell arteritis and treatment was initiated with corticoids. The patient evolved favourably in the clinical and radiological follow-up.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francisco Javier García-Gómez, Irene Acevedo-Báñez, Rubén Martínez-Castillo, Manuel García-Gutiérrez, Juan Luis Tirado-Hospital, Isabel Borrego-Dorado" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Francisco Javier" "apellidos" => "García-Gómez" ] 1 => array:2 [ "nombre" => "Irene" "apellidos" => "Acevedo-Báñez" ] 2 => array:2 [ "nombre" => "Rubén" "apellidos" => "Martínez-Castillo" ] 3 => array:2 [ "nombre" => "Manuel" "apellidos" => "García-Gutiérrez" ] 4 => array:2 [ "nombre" => "Juan Luis" "apellidos" => "Tirado-Hospital" ] 5 => array:2 [ "nombre" => "Isabel" "apellidos" => "Borrego-Dorado" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775314006691" "doi" => "10.1016/j.medcli.2014.09.004" "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/S0025775314006691?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020615003654?idApp=UINPBA00004N" "url" => "/23870206/0000014500000002/v1_201602250041/S2387020615003654/v1_201602250041/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial article</span>" "titulo" => "Cholesterol associated to low density lipoproteins (LDL) and vascular risk reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9): A new therapeutic target" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "67" "paginaFinal" => "69" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Carlos Guijarro, Luis Miguel Ruilope" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Carlos" "apellidos" => "Guijarro" "email" => array:1 [ 0 => "cguijarro@fhalcorcon.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Luis Miguel" "apellidos" => "Ruilope" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Medicina Interna, Consulta de Riesgo Vascular, Hospital Universitario Fundación Alcorcón, Universidad Rey Juan Carlos, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Investigación, Unidad de Hipertensión, Hospital Universitario 12 de Octubre, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Colesterol ligado a lipoproteínas de baja densidad (LDL) y reducción del riesgo vascular. Proproteína convertasa subtilisina / Kexina tipo 9 (PCSK9): una nueva diana terapéutica" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Cardiovascular diseases continue to be the leading cause of mortality and a major cause of morbidity in Spain.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> High concentrations of total cholesterol, and specifically cholesterol associated with low density lipoproteins (LDL), have a positive and increasing association for all standard levels in the Western population, with the development of ischaemic cardiopathy and cardiovascular mortality.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> The lipid hypothesis regarding atherosclerosis has been powerfully endorsed by a large number of clinical trials which have shown consistently that the reduction of total cholesterol (and LDL cholesterol) is associated with a reduction in the risk of coronary heart failure, ictus and cardiovascular mortality.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> The most consistent data are those obtained from clinical trials with statins, both in primary prevention and secondary prevention.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> In addition, intensive statin treatment has been shown to have superior protective effects than medium or low dose treatment.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> Despite the unquestionable triumph of statins, the majority of trials show that a reduction of relative risk is around 30%. The other 70% is what is normally referred to as “residual risk” but which should perhaps more appropriately be called “persistent risk”.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Although it is misleading to attempt to completely control a multifactorial disease such as atherosclerosis by treating a single risk factor, it is reasonable to suggest that hypolipidemic treatment still offers potentially protective options.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">6,7</span></a> In this sense, we may recall that the rise in HDL cholesterol in epidemiological trials is clearly associated with the reduction of cardiovascular complications.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Unfortunately the majority of therapeutic trials aimed at raising cholesterol linked to high density lipoproteins (HDL) have had disappointing results, particularly in trials recently conducted with patients who are already being treated with statins and using differently pharmacological groups such as fibrates, niacin or cholesteryl ester transfer protein inhibitors.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Recent genetic studies have contested the aetiological role of HDL cholesterol lowering in the development of atherosclerosis.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> Mendelian randomisation studies offer an opportunity to make an assessment of the relevance of different mutations which modify several risk factors from birth and their repercussion on the development of atherosclerosis through “natural experiments”.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> For example, these studies support the relevance of lipoprotein (a) [Lp(a)] but not that of C-reactive protein in the aetiology of atherosclerosis. Similar trials show that genetic changes which since birth modify HDL cholesterol levels are not associated with an increase or decrease in cardiovascular complications.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">9,10</span></a> These studies do not contradict that HDL cholesterol levels are vascular risk markers but they do question their relevance in the aetiology of vascular lesión. On the contrary, mendelian randomisation studies do show a clear and coherent relationship between diverse genes which alter LDL cholesterol levels and the development of atherosclerosis<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a>, and very notably the genes involved in synthesis (HMG-CoA reductase) and absorption (<span class="elsevierStyleItalic">Niemann-Pick C1-Like 1</span> [NPC1L1]) of cholesterol, and degradation of the proprotein convertase subtilisin/kexin type 9 (PCSK9) LDL receptor.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11,12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Recent European and North American guidelines on dyslipidemias diverge on several aspects, but coincide on showing LDL cholesterol as a therapeutic target and priority in treatment with statins.<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">13,14</span></a> The most compelling issue is whether we can achieve higher LDL cholesterol reductions with other therapeutic options and whether these will be interpreted as a reduction of cardiovascular complications.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The beneficial effects and treatment limitations with statins have been extensively assessed. The unquestionable success of statins has triggered the paradoxical reaction of almost cancelling out the possible therapeutic value of other hypolipidemic drugs.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> However, one aspect which has received very little attention is that statins trigger the counter regulation of genes which lessen their hypolipidemic effect. Of these, the most outstanding are the genes regulating the before-mentioned proteins NP1CL1 and PCSK9,<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> and which in turn, are epidemiologically linked to changes in LDL cholesterol levels and cardiovascular morbidity.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">10–12</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The protein NPC1L1 is involved in the intestinal transport of cholesterol, and its up-regulation therefore lowers the effect of the statins. Specifically, NPC1L1 is ezetimibe's target, a cholesterol-absorption inhibitor. Ezetimibe is a drug which is generally well tolerated, which alone or associated with statins produces a moderate LDL cholesterol reduction of 15–20%. The ezetimibe–simvastatin combination has demonstrated a reduction of cardiovascular complications in patients with kidney failure<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> or aortic estenosis.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> However, the design of the before-mentioned studies were not able to ascertain whether or not a cardiovascular protective component was attributable to ezetimibe in addition to that expected from the statin. The effect of ezetimibe on cardiovascular events, compared with placebo, was evaluated in the recently published IMPROVE-IT study.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> Findings indicate that treatment with ezetimibe (associated with simvastatin) in patients with acute coronary syndrome associated with a reduction of cardiovascular complications compared with placebo of similar magnitude to that expected by the reduction of LDL cholesterol. This important study verifies the cardiovascular protective factor of the hypolipidemic action of ezetimibe and increases its benefit to levels within the range of 50–55<span class="elsevierStyleHsp" style=""></span>mg/dl of LDL cholesterol.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Another gene of interest whose expression increases after treatment with statins is the one encoding PCSK9.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> PCSK9 is serine protease secreted by the liver which binds with the LDL receptor and contributes to its lysosomal decline.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">When PCSK9 is absent, the LDL is internalised by the receptor, degraded in the cytoplasm and the LDL receptor recycles to the cellular membrane to continue attracting LDL particles. In the presence of PCSK9 the LDL receptor is guided towards its degradation in the lysosome. The presence of PCSK9 is therefore associated with the reduction of LDL receptors, and an increase in LDL cholesterol in plasma. Hardly less than a decade ago, it was reported for the first time that there were agents which showed an increased expression of PCSK9 which exhibited a similar phenotype to that of patients with familial hypercholesterolemia due to mutations in the LDL receptor.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> On the contrary, people with a defective gene in PCSK9 are apparently normal subjects, but with abnormally low levels of LDL cholesterol and a marked reduction in vascular risk.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> It would therefore seem that the suppression of the action of PCSK9 is a very appealing therapeutic target in patients with hypercholesterolemia. In fact, preliminary studies (phase 1) have demonstrated that inhibition of PCSK9 synthesis with RNA interference is associated with a reduction of PCSK9 circulating at 70% and concomitantly of LDL cholesterol at 40%.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> The development of PCSK9 binding to the LDL receptor inhibitors is still in an incipient phase.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> However, the therapeutic option for blocking PCSK9 which is currently most developed is the use of human monoclonal antibodies aimed at PCSK9. Several of these components, and in particular alirocumab (REGN727/SAR236553, Sanofi Regeneron) and evolocumab (AMG145, Amgen), have been assessed in phase II/III clinical trials against a placebo in patients with primary hypercholeserolemia.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">24–27</span></a> The subcutaneous administration of the antibodies every 2 or 4 weeks for several months appears to be well tolerated and with LDL cholesterol lowering of between 50% and 70%, either in monotherapy or based on statin treatments with or without ezetimibe. It is of note that the PCSK9 antibodies result in significant lowering of Lp(a) by mechanisms which are not totally clear. Two randomised studies have recently been published with anti-PCSK9 human antibodies which have explored their possible effect on cardiovascular disease prevention. The OSLER trials 1 and 2 are 2 open-label randomised trials which have evaluated the hypolipidemic action of evolocumab and in a “pre-defined exploratory manner”, its effect on cardiovascular complications after median follow-up of 11.1 months. Treatment with evolocumab is associated with a drop in LDL cholesterol of 61% (pre and post treatment medians of 120 and 48<span class="elsevierStyleHsp" style=""></span>mg/dl, respectively) and a reduction of cardiovascular complications close to 50% (cause of risk 0.47; 95% confidence level 0.28–0.78; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.003).<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Notwithstanding, the long-term ODYSSEY is the only double-blind, randomised, phase III clinical trial published to date which evaluates the effects of alirocumab against a placebo with a main variable of efficacy on cardiovascular effects.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> An ad hoc analysis of this study, made at 78 weeks follow-up (prior to its foreseeable termination) has shown that alirocumab is associated with a drop in LDL cholesterol of 62% (placebo 118.9<span class="elsevierStyleHsp" style=""></span>mg/dl; alirocumab 48.3<span class="elsevierStyleHsp" style=""></span>mg/dl) and a reduction of cardiovascular complications around 50% (cause of risk, 0.52; 95% confidence interval 0.31–0.90; <span class="elsevierStyleItalic">p</span> nominal<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.02). Although all post hoc analysis has to be cautiously interpreted, the double-blind nature of the study and coherence with evolocumab findings suggest findings are robust.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The reported outcome shows a coherent reduction in cardiovascular episodes with lowering of cholesterol obtained using ezetimibe or anti-PCSK9, similarly to the outcome with statins (figure, available as Appendix A on the web). In addition, hypolipidemic treatment benefits are extended to LDL cholesterol levels of around 50<span class="elsevierStyleHsp" style=""></span>mg/dl, over and above the optimum levels considered up until now in all cardiovascular prevention guidelines.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Further studies are needed to evaluate the safety of the anti-PCSK9 antibodies and especially their effect on the development of atherosclerosis and cardiovascular complications in long term studies. The potential target of these drugs is the group of patients who are intolerant to statins and high vascular risk patients where treatment with statins is considered insufficient, including heterozygous familial hypercholesterolemia. Since the mechanism of action of anti-PCSK9 drugs requires the presence of functioning LDL receptors, it would seem that their use will be more limited in patients with heterozygous familial hypercholesterolemia or double heterozygote.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> In contrast, for the remainder of the population, if the natural protective effect of patients defective in PCSK9 could be reproduced through the pharmacological neutralisation of PCSK9 using monoclonal anti-bodies (or other mechanisms), we could be witnessing a new qualitative jump in hypolipidemic treatment which could emulate (or exceed) the success of statins. With the complementary mechanisms of action, the triple therapy with statins, absorption inhibitors and anti-PCSK9 agents could achieve reductions in LDL cholesterol of approximately 80–90%. The question as to how far we can continue reducing LDL cholesterol with a favourable risk/benefit balance remains an open one and major advances for the near future look promising.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Guijarro C, Ruilope LM. Colesterol ligado a lipoproteínas de baja densidad (LDL) y reducción del riesgo vascular. Proproteína convertasa subtilisina / Kexina tipo 9 (PCSK9): una nueva diana terapéutica. Med Clin (Barc). 2015;145:67–69.</p>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0065" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0010" ] ] ] ] "multimedia" => array:1 [ 0 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 146202 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Las enfermedades cardiovasculares y sus factores de riesgo en España: hechos y cifras. 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