Vascular calcification: types and mechanisms
Calcificación vascular: tipos y mecanismos
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Valdivielso" "autores" => array:1 [ 0 => array:4 [ "Iniciales" => "J.M." "apellidos" => "Valdivielso" "email" => array:1 [ 0 => "valdivielso@medicina.udl.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitari Arnau de Vilanova. IRBLLEIDA, Lleida, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Calcificación vascular: tipos y mecanismos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10754_108_18596_en_10754_f1_en.jpg" "Alto" => 203 "Ancho" => 264 "Tamanyo" => 11800 ] ] "descripcion" => array:1 [ "en" => "Model of the effects of calcium and phosphorus on the mineralisation of VSMC." ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION    </span></p><p class="elsevierStylePara">Calcium phosphate may be deposited as bioapatite crystals  (similar to bone) in blood vessels and heart valves in  vascular calcification.<span class="elsevierStyleSup">1 </span>Traditionally, calcification has been  classified depending on where the calcium was deposited. In  this way, arterial calcification has been divided into intimal  calcification (associated with atheromatous plaques<span class="elsevierStyleSup">2</span>) and  medial calcification (known as Mönckeberg’s sclerosis)  linked to vascular stiffness due to the mineralisation of  elastic fibres and atherosclerosis seen with age, diabetes and  chronic kidney disease (CKD).<span class="elsevierStyleSup">3 </span>The first one would be  linked to an increased deposit of lipids and inflammatory cell  infiltrate, while the phenotypic transformation of vascular  smooth muscle cells towards osteoblast-like cells would be  more important in the second one. A mixture of both calcifications is seen in patients with CKD.<span class="elsevierStyleSup">4,5 </span>However,  recent results seem to suggest that this classification is not  very clear and that both would be manifestations of the  atherosclerotic process,<span class="elsevierStyleSup">6 </span>at least in great arteries.  Mönckeberg first described this in 1903.<span class="elsevierStyleSup">7 </span>He described in his  article the presence of calcification in the middle layer of 18  patients’ arteries with no evidence of plaque. However, the  description was made without the help of modern-day  techniques to measure lipid deposit, extracellular matrix, etc.  It would not be too far fetched to think that what he was  actually describing was different stages in the evolution of  atherosclerotic plaque. However, several studies have  described patients with Mönckeberg’s sclerosis in the last  few years.<span class="elsevierStyleSup">8-12 </span>If we analyse these studies in detail, we can  come to the conclusion that there are characteristics of  atherosclerotic lesions in nearly all of them: increased  intima-media thickness, disruption of the internal elastic  lamina or even lipid deposits. Furthermore, the great arteries  have a middle layer with a low number of vascular smooth  muscle cells. They are, therefore, more sensitive to the  atherosclerotic process than to phenotypic transformation  towards osteoblast-like cells. </p><p class="elsevierStylePara">A recent study by our group using ultrasound, the only noninvasive  method to determine the exact location of vascular  calcifications, shows that vascular calcification of capacitance  arteries is associated with the presence of atherosclerosis.<span class="elsevierStyleSup">13 </span>In  this paper, we have studied the presence of vascular  calcifications and atheromatous plaques in carotid, femoral and  brachial arteries in 232 patients and 208 control patients. The  most common type of vascular calcification was linear  calcification of the intima, followed by atheromatous plaque  calcification. What seemed to be a new type of vascular  calcification is not, in fact, since calcification of the internal  elastic lamina had histologically already been described in  coronary arteries.<span class="elsevierStyleSup">11 </span>Another important result was that linear  calcification of the intima was intimately associated with the  presence of plaques, as it was not found in radial arteries (which  do not develop atherosclerosis). The study also concluded that  absence of carotid plaque was a protective factor. Therefore, our  results seem to indicate that the predominant type of vascular  calcification of great arteries in patients on dialysis is associated  with the presence of atherosclerosis.   </p><p class="elsevierStylePara"><span class="elsevierStyleBold">VASCULAR CALCIFICATION MECHANISMS    </span></p><p class="elsevierStylePara">Vascular calcification is an active and regulated process that  involves different mechanisms that are not mutually  exclusive.<span class="elsevierStyleSup">14  </span><span class="elsevierStyleBold">  </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Calcium and phosphorus  </span>  </p><p class="elsevierStylePara">Some authors refer to them as “passive mechanisms of  calcification”. Elevated levels of Ca, P and CaxP (prevalent in patients with CKD and significantly associated with death  due to cardiovascular disease [CVD] in these patients<span class="elsevierStyleSup">15</span>)  cause clusters of bioapatite crystals to form and grow.<span class="elsevierStyleSup">16  </span>Bioapatite is the main mineral component of bones, fish  bones and shells. <span class="elsevierStyleItalic">In vitro </span>studies found that when VSMC  were incubated with high concentrations of calcium or  phosphorus, bioapatites accumulated in the extracellular  matrix. When they were incubated with both elements at the  same time, a synergistic effect of calcification was  observed.<span class="elsevierStyleSup">17 </span>However, this process is not just a passive  precipitation of divalent ions, but rather a phenotypic change  of VSMC and the up-regulation of genes commonly  associated with bone differentiation.<span class="elsevierStyleSup">18 </span>The effects of  hyperphosphataemia are mediated by a sodium-dependent  phosphate cotransporter (NPC). Type III NPC, Pit-1, has  been found in VSMC. High phosphorus levels stimulate the  load while elevated calcium levels increases the Pit-1 mRNA  expression. This transporter allows phosphorus to  accumulate within cells, which acts as a signal for the  expression of osteogenic genes. This causes mineral  molecules to be secreted (matrix vesicles, calcium-binding  proteins, alkaline phosphatase and collagen-rich extracellular  matrix). The combination of these factors induces the cell to  change and become susceptible to calcification (Figure 1).  <span class="elsevierStyleBold">  </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Cell death and apoptosis  </span>  </p><p class="elsevierStylePara">Vascular calcification is linked to the appearance of matrix  vesicles with cytoplasmic content and intact cell membrane  (as happens in bone development). These vesicles are  formed from cells where mineralisation starts or they are the  result of the cell apoptosis process (apoptotic bodies). The  wall of uraemic patients is damaged by inflammation  processes and oxidative stress and one may therefore think that there is cell apoptosis. Proudfoot et al.<span class="elsevierStyleSup">19 </span>showed that  apoptosis regulates vascular calcification <span class="elsevierStyleItalic">in vitro</span>. According  to these authors, matrix vesicles are capable of concentrating  calcium inside and bioapatite crystals originate in them.  <span class="elsevierStyleBold">  </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Calcification inhibitors  </span>  </p><p class="elsevierStylePara">Under normal conditions blood vessel cells express  mineralisation-inhibiting molecules. The loss of their  expression, as happens in CKD, causes what is known as  “loss of natural inhibition”, giving rise to spontaneous  calcification and increased mortality. A list with these  calcification-inhibiting molecules has been drawn up after  mutation analysis on mice, including among others:    </p><p class="elsevierStylePara">Matrix Gla Protein </p><p class="elsevierStylePara">Matrix Gla Protein (MGP) was the first calcification  inhibitor to be identified. It is a vitamin K-dependant protein  that is constitutively expressed in VSMC and endothelial  cells of normal blood vessels, but its expression is greatly  reduced in calcified arteries.<span class="elsevierStyleSup">20 </span>It has also been observed that  its expression is reduced in <span class="elsevierStyleItalic">in vitro </span>calcification models.<span class="elsevierStyleSup">21  </span>Serum MGP levels are lower in patients with calcifications  than in those without it.<span class="elsevierStyleSup">22 </span>Furthermore, MGP knockout mice  develop severe medial calcifications and die of a ruptured  aorta.<span class="elsevierStyleSup">23  </span>  </p><p class="elsevierStylePara">Fetuin A </p><p class="elsevierStylePara">Fetuin A is a serum glycoprotein that inhibits ectopic  vascular calcification. It is a powerful inhibitor of  hydroxyapatite formation, reducing the formation of crystals  in <span class="elsevierStyleItalic">in vitro </span>solutions containing calcium and phosphorus  without affecting those that are already formed.<span class="elsevierStyleSup">24 </span>Mice that  are deficient in this protein develop extensive calcifications  in soft tissue such as the myocardium, kidneys, tongue and  skin.<span class="elsevierStyleSup">25  </span>  </p><p class="elsevierStylePara">Osteopontin </p><p class="elsevierStylePara">Osteopontin (OPN) is a phosphoprotein that is usually  found in mineralised tissue such as bones and teeth, and is  involved in regulating mineralisation as it inhibits apatite  crystal growth.<span class="elsevierStyleSup">26 </span>Although it is not found in normal arteries,  some authors have detected its expression in atherosclerotic  plaques and calcified aortic valves.<span class="elsevierStyleSup">27-29 </span>Giachelli et al.<span class="elsevierStyleSup">30  </span>crossed OPN-/- mutant mice (that had no vascular  symptoms) with MGP-/- mutant mice (that had developed  vascular calcifications) to examine the role of OPN in  vascular calcification. OPN-/- MGP-/- mice showed a more  accelerated calcification than those that were only deficient  in MGP (MGP-/- OPN+/+). These studies, therefore,  indicate that OPN is an inducible inhibitor of vascular  calcification <span class="elsevierStyleItalic">in vivo</span>.    </p><p class="elsevierStylePara">Osteoprotegerin </p><p class="elsevierStylePara">Osteoprotegerin (OPG) is a member of the tumour  necrosis factor receptor family that has been identified as a  regulator of bone resorption.<span class="elsevierStyleSup">31 </span>OPG is produced by many  tissues, including the cardiovascular system, lungs, kidney  and immune system.<span class="elsevierStyleSup">32 </span>In advanced calcified lesions, OPG  is found around the calcified area. It has been seen that  OPG-deficient mice develop severe osteoporosis and  medial calcification.<span class="elsevierStyleSup">33 </span>Therefore, OPG is obviously an  inhibitor of vascular calcification. The potential of OPG as  a marker of cardiovascular disease has been studied. As  the severity of vascular calcification increases so does the  serum OPG level.<span class="elsevierStyleSup">34 </span>OPG functions as a soluble decoy  receptor for the receptor activator of NF-kB (RANK)  ligand (RANKL).<span class="elsevierStyleSup">32 </span>RANKL is produced by activated T  cells and stimulates RANK. This activation enables,  among others, an increased expression of inflammation  mediators. In addition, OPG is a receptor for tumour  necrosis factor-related apoptosis-inducing ligand (TRAIL),  which is a powerful apoptosis inducer. TRAIL is found in  many different tissues, including VSMC and endothelial  cells. In human atherosclerotic lesions, TRAIL has been  located around calcified areas.<span class="elsevierStyleSup">9  </span><span class="elsevierStyleBold">  </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Calcification activators  </span>  </p><p class="elsevierStylePara">There are studies that speculate that, as well as  hyperphosphataemia and hypercalcaemia, there are  substances present in the blood serum of patients with CKD  capable of stimulating calcification.<span class="elsevierStyleSup">35 </span>Bovine VSMC in the  presence of uraemic serum increases the expression of  calcification-related proteins. A large number of uraemic  factors have been identified that are capable of inducing  osteogenic genes, transforming osteoblasts and secreting  some bone matrix proteins in the walls of blood vessels and  soft tissue. Some of these factors are: tumour necrosis factor  (TNF),<span class="elsevierStyleSup">36 </span>inflammatory cytokines,<span class="elsevierStyleSup">37 </span>fibronectin,<span class="elsevierStyleSup">38 </span>type-I  collagen<span class="elsevierStyleSup">38 </span>and 25-hydroxycholesterol.<span class="elsevierStyleSup">39 </span>These uraemic serum  substances stimulate the expression of molecules essential to  vesicular calcification.    </p><p class="elsevierStylePara">Alkaline phosphatase </p><p class="elsevierStylePara">Alkaline phosphatase (ALP) is one of the osteoblastic  phenotype markers and is considered essential in the  vascular calcification process. It has been detected in  vascular and heart valve calcifications. ALP expressed on  the surface of cells can act on phosphate liberators, releasing inorganic phosphate.<span class="elsevierStyleSup">40 </span>Inflammatory cytokines  and vitamin D induce its up-regulation and  mineralization.<span class="elsevierStyleSup">40,41  </span>  </p><p class="elsevierStylePara">Core-binding factor alpha 1 </p><p class="elsevierStylePara">Core-binding factor alpha 1 (Cbfa1) is the main regulator  of bone cell differentiation. Cbfa1-deficient mice have  problems with cartilage formation and bone  mineralisation.<span class="elsevierStyleSup">42 </span>It acts as a transcription factor that  accelerates the expression of important osteoblast lineage  genes such as osteocalcin, osteopontin, ALP or type-I  collagen.<span class="elsevierStyleSup">20 </span>Its expression is up-regulated by phosphate<span class="elsevierStyleSup">43  </span>and uraemic toxins.<span class="elsevierStyleSup">35  </span><span class="elsevierStyleItalic">  </span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic">Bone morphogenic proteins  </span></p><p class="elsevierStylePara">Bone morphogenic proteins (BMP) are a group of, at  least, 30 proteins that receive their name from their  osteoinductive properties. BMP belong to the  transforming growth factor-beta (TGF-‚) superfamily.  They act by binding to a heterodimeric system of  transmembrane receptors (BMP-1 and BMP-2 receptor)  that trimerises upon binding. The binding of a BMP to its  specific type II receptor results in the type 1 receptor  being activated. This causes phosphorylation and nuclear  translocation of the Smad transcription factors thus  modifying the transcription rate of target genes.<span class="elsevierStyleSup">44 </span>They  then induce ectopic bone formation.<span class="elsevierStyleSup">45  </span></p><p class="elsevierStylePara">BMP2 is a powerful bone morphogenic protein and its  expression triggers osteogenic transcriptional regulatory  programs in the arterial tree. BMP2 induces Msx2 as well  as Cbfa1 in VSMC.<span class="elsevierStyleSup">46 </span>Msx2 is needed for the formation of  intramembranous bones and it is critical for osteoblast  differentiation, endochondral bone formation and  neovascularisation. </p><p class="elsevierStylePara">They were recognised as mediators of vascular  calcification long ago: BMP2 and BMP4 are involved in  mineralisation and induction of local inflammation, while  BMP7 slows down vascular calcification. BMPs are  expressed in different cells in atherosclerotic lesions as  well as in endothelial lesions and VSMC.<span class="elsevierStyleSup">47,48 </span>The effect of  BMP2 on vascular calcification is inhibited by MGP.<span class="elsevierStyleSup">49  </span><span class="elsevierStyleBold">  </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">RANKL  </span>  </p><p class="elsevierStylePara">RANKL (also known as OPGL) is a protein consisting of  316 amino acids with a molecular weight of 38kD. Its  expression is also modulated by several cytokines,  glucocorticoids and PTH.<span class="elsevierStyleSup">50 </span>RANKL is produced by  osteoblast lineage cells and activated T cells. It promotes osteoclast formation, fusion, differentiation, activation and  survival, leading to increased bone resorption and bone  loss.<span class="elsevierStyleSup">51 </span>RANKL stimulates its specific receptor RANK, which  is expressed in fewer cells such as progenitor cells and  mature osteoclasts, activated T cells and dendritic cells.<span class="elsevierStyleSup">52-54  </span>The activation of RANK by RANKL triggers the NF-κB  intracellular signalling cascade. The final stage of RANK  activation is the NK-κB translocation into the nucleus, which  can take place by the classical or alternative pathway. Both  pathways are regulated by their kinases which are,  respectively, IKK‚ and IKKα. The NK-κB translocation to  the nucleus modulates the expression of different genes, e.g.  BMP4 (Figure 2).<span class="elsevierStyleSup">55  </span></p><p class="elsevierStylePara">The biological effects of OPG are the opposite of  RANKL-mediated effects, due to the fact that OPG acts  as a soluble inhibitor that prevents RANKL interaction  and the subsequent stimulation of its RANK receptor.<span class="elsevierStyleSup">56  </span></p><p class="elsevierStylePara">The first signs that this system was involved in vascular  calcification came out of a study on OPG-knockout  mice, which had osteoporosis and calcifications of the  aorta and kidney arteries.<span class="elsevierStyleSup">33 </span>OPG expression can be found  in the media of great arteries<span class="elsevierStyleSup">31 </span>and in many different  types of blood vessel cells, such as VSMC and  endothelial cells.<span class="elsevierStyleSup">57,58 </span>It has been proven that it acts as an  autocrine survival factor in endothelial cells.<span class="elsevierStyleSup">58 </span>In  contrast, RANKL and RANK have only been found in  calcified areas of transgenic mice, in the arteries of wild  mice.<span class="elsevierStyleSup">59 </span>Other studies have demonstrated that OPG  inhibits vascular calcification in <span class="elsevierStyleItalic">in vivo </span>rats caused by  both vitamin D and warfarin.<span class="elsevierStyleSup">60 </span>The definitive proof that  RANKL directly promotes vascular calcification came in  2009, when one of the studies from our laboratory  proved that RANKL directly increases calcification of  VSMC by increasing BMP4 expression. This increased  expression is due to the activation of the alternative NFkB  signalling pathway. </p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">KEY CONCEPTS  </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">1. </span>Recent results seem to indicate that vascular  calcification is always associated with the presence  of atheromatous plaques in great arteries,  more than with mineral metabolism disorders.  This does not rule out that mineral  metabolism disorders might intensify vascular  calcification. </p><p class="elsevierStylePara"><span class="elsevierStyleBold">2. </span>Pro-calcifying and anti-calcifying mechanisms  play an important role in the pathophysiology  of vascular calcification. Therapies that aim to  reduce vascular calcification in patients on  dialysis should be directed at trying to reduce  atherosclerosis as well as restoring anti-calcifying  mechanisms or inhibiting pro-calcifying  mechanisms. </p><p class="elsevierStylePara"><a href="grande/10754_108_18596_en_10754_f1_en.jpg" class="elsevierStyleCrossRefs"><img src="10754_108_18596_en_10754_f1_en.jpg" alt="Model of the effects of calcium and phosphorus on the mineralisation of VSMC."></img></a></p><p class="elsevierStylePara">Figure 1. Model of the effects of calcium and phosphorus on the mineralisation of VSMC.</p><p class="elsevierStylePara"><a href="grande/10754_108_18597_en_10754_f2_en.jpg" class="elsevierStyleCrossRefs"><img src="10754_108_18597_en_10754_f2_en.jpg" alt="Diagram of the activation of RANK by RANKL."></img></a></p><p class="elsevierStylePara">Figure 2. Diagram of the activation of RANK by RANKL.</p>" "pdfFichero" => "P1-E518-S2894-A10754-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441231" "palabras" => array:1 [ 0 => "Calcificación de la íntima" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441233" "palabras" => array:1 [ 0 => "Calcificación de la media" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441235" "palabras" => array:1 [ 0 => "Enfermedad renal crónica" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441237" "palabras" => array:1 [ 0 => "Calcificación vascular" ] ] ] "en" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441232" "palabras" => array:1 [ 0 => "Intimal calcification" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441234" "palabras" => array:1 [ 0 => "Medial calcification" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441236" "palabras" => array:1 [ 0 => "End stage renal disease" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441238" "palabras" => array:1 [ 0 => "Vascular calcification" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">Vascular calcification has traditionally been considered to be a passive process that was associated with advanced age, atherosclerosis, uncommon genetic diseases and some metabolic alterations such as diabetes mellitus and end-stage kidney failure. However, in the last years, vascular calcification has been proven to be an active and regulated process, similar to bone mineralisation, in which different bone-related proteins are involved. Recent results question the classic classification of vascular calcification into intimal and medial calcification, at least in capacitance arteries. Pro and anti-calcifying mechanisms play an active role in calcium deposition in vascular cells, making this area an active focus of research. The identification of therapeutic targets which can slow down the progression or even reverse vascular calcification could be an important step forward in the treatment of patients with chronic kidney disease.</p>" ] "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">Clásicamente se consideraba que la calcificación vascular era un proceso pasivo y degenerativo que frecuentemente ocurría con la edad avanzada, aterosclerosis, varias alteraciones metabólicas (como diabetes mellitus y estados finales de enfermedad renal) y en raras enfermedades genéticas. Sin embargo, desde hace algunos años, la calcificación vascular es considerada como un proceso activo y regulado de manera semejante a la mineralización y metabolismo del hueso, en el se encuentran implicadas diversas proteínas óseas. Resultados recientes cuestionan la clásica separación de la calcificación vascular en calcificación de la íntima y calcificación de la media, al menos en arterias de capacitancia. Mecanismos procalcificantes y anticalcificantes desempeñan un papel activo en la deposición de calcio en las células vasculares, por lo que su estudio se ha convertido en un área muy activa de investigación. La identificación de dianas terapéuticas que puedan enlentecer o incluso revertir la calcificación vascular podría suponer un avance muy importante en las estrategias terapéuticas para los pacientes afectados de enfermedades renales.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10754_108_18596_en_10754_f1_en.jpg" "Alto" => 203 "Ancho" => 264 "Tamanyo" => 11800 ] ] "descripcion" => array:1 [ "en" => "Model of the effects of calcium and phosphorus on the mineralisation of VSMC." ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10754_108_18597_en_10754_f2_en.jpg" "Alto" => 187 "Ancho" => 264 "Tamanyo" => 14007 ] ] "descripcion" => array:1 [ "en" => "Diagram of the activation of RANK by RANKL." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Giachelli CM. 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