Absence of cystatin C involvement in ventricular remodelling and heart failure

array:23 ["pii" => "S225488741500123X" "issn" => "22548874" "doi" => "10.1016/j.rceng.2015.12.002" "estado" => "S300" "fechaPublicacion" => "2016-03-01" "aid" => "1215" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "copyrightAnyo" => "2015" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Rev Clin Esp. 2016;216:55-61" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2 "PDF" => 2 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0014256515002751" "issn" => "00142565" "doi" => "10.1016/j.rce.2015.11.003" "estado" => "S300" "fechaPublicacion" => "2016-03-01" "aid" => "1215" "copyright" => "Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Rev Clin Esp. 2016;216:55-61" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 232 "formatos" => array:2 [ "HTML" => 19 "PDF" => 213 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "ORIGINAL" "titulo" => "Ausencia de implicación de la cistatina C en el remodelado ventricular y la insuficiencia cardiaca" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "55" "paginaFinal" => "61" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Absence of cystatin C involvement in ventricular remodelling and heart failure" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1415 "Ancho" => 1954 "Tamanyo" => 575850 ] ] "descripcion" => array:1 [ "es" => "Tinción inmunohistoquímica de las muestras de tejido miocárdico (x20). A) Hematoxilina de contraste y diluyente de anticuerpos (control). Se observan miocitos cardiacos de estructura normal con los núcleos teñidos débilmente ocupando una posición central dentro de la célula, con tinción de fondo de hematoxilina. También se observa pigmento de lipofuscina en los polos del núcleo (Ac x20). B) Desmina en miocardio fetal: la expresión de desmina es mucho más débil que en el corazón adulto o es negativa traduciendo probablemente una falta de desarrollo de las sarcómeras. C) Desmina en miocardio adulto: estriación transversal de todo el miocardio; las bandas intercalares destacan más oscuras. D) MMP9 en miocardio fetal: la inmunotinción citoplásmica para MMP9 es positiva en células aisladas en el intersticio. El citoplasma de las células musculares es negativo. E) MMP9 en miocardio adulto: inmunotinción citoplásmica para MMP9 en células aisladas en el intersticio; las células musculares son negativas. F) CisC en miocardio fetal: se aprecia una celularidad más abundante que en el corazón adulto con disposición menos ordenada de las células y una leve inmunotinción citoplásmica de los miocardiocitos para CisC. Existe alguna célula pequeña aislada en el intersticio que expresa cistatina en su citoplasma. G) CisC en miocardio adulto: cardiomiocitos inmunoteñidos con expresión difusa de CisC en el citoplasma." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.I. Pérez-Calvo, T. Castiella Muruzábal, M. Búcar Barjud, C. Josa Laorden, M. Sánchez Marteles, I. Lacambra Blasco, M.C. Asensio López, D.A. Pascual Figal" "autores" => array:8 [ 0 => array:2 [ "nombre" => "J.I." "apellidos" => "Pérez-Calvo" ] 1 => array:2 [ "nombre" => "T." "apellidos" => "Castiella Muruzábal" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Búcar Barjud" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Josa Laorden" ] 4 => array:2 [ "nombre" => "M." 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Torres-Sánchez, E. Ávila-Barranco, R.J. Esteban de la Rosa, R. Fernández-Castillo, M.A. Esteban, J.J. Carrero, M. García-Valverde, J.A. Bravo-Soto" "autores" => array:9 [ 0 => array:2 [ "nombre" => "M.J." "apellidos" => "Torres-Sánchez" ] 1 => array:2 [ "nombre" => "E." "apellidos" => "Ávila-Barranco" ] 2 => array:2 [ "nombre" => "R.J." "apellidos" => "Esteban de la Rosa" ] 3 => array:2 [ "nombre" => "R." "apellidos" => "Fernández-Castillo" ] 4 => array:2 [ "nombre" => "M.A." "apellidos" => "Esteban" ] 5 => array:2 [ "nombre" => "J.J." "apellidos" => "Carrero" ] 6 => array:2 [ "nombre" => "M." "apellidos" => "García-Valverde" ] 7 => array:2 [ "nombre" => "J.A." "apellidos" => "Bravo-Soto" ] 8 => array:1 [ "colaborador" => "en representación del Grupo para el Estudio de la Enfermedad Poliquística Autosómica Dominante (GEEPAD)" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256515002337" "doi" => "10.1016/j.rce.2015.09.007" "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/S0014256515002337?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S225488741500106X?idApp=WRCEE" "url" => "/22548874/0000021600000002/v1_201603010018/S225488741500106X/v1_201603010018/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Absence of cystatin C involvement in ventricular remodelling and heart failure" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "55" "paginaFinal" => "61" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J.I. Pérez-Calvo, T. Castiella Muruzábal, M. Búcar Barjud, C. Josa Laorden, M. Sánchez Marteles, I. Lacambra Blasco, M.C. Asensio López, D.A. Pascual Figal" "autores" => array:8 [ 0 => array:4 [ "nombre" => "J.I." "apellidos" => "Pérez-Calvo" "email" => array:1 [ 0 => "jiperez@unizar.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "T." "apellidos" => "Castiella Muruzábal" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M." "apellidos" => "Búcar Barjud" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "C." "apellidos" => "Josa Laorden" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "M." "apellidos" => "Sánchez Marteles" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "I." "apellidos" => "Lacambra Blasco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 6 => array:3 [ "nombre" => "M.C." "apellidos" => "Asensio López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] 7 => array:3 [ "nombre" => "D.A." "apellidos" => "Pascual Figal" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa Facultad de Medicina, Instituto de investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Clínico Universitario Lozano Blesa Facultad de Medicina, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Instituto de investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Cardiología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca Facultad de Medicina, Murcia, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Ausencia de implicación de la cistatina C en el remodelado ventricular y la insuficiencia cardiaca" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1415 "Ancho" => 1955 "Tamanyo" => 561871 ] ] "descripcion" => array:1 [ "en" => "Immunohistochemistry staining of myocardial tissue samples (20×). (A) Contrast hematoxylin and antibody diluent (check-up). We can see cardiac myocytes with normal structures and weakly stained nuclei occupying a central position within the cells, with background hematoxylin staining. We can also see lipofuscin pigment in the poles of the nucleus (Ab 20×). (B) Desmin in fetal myocardium: desmin expression is much weaker than in the adult heart or is negative, which likely translates into a lack of development of the sarcomeres. (C) Desmin in adult myocardium: cross striations throughout the myocardium; the intercalated bands show up as darker. (D) MMP9 in fetal myocardium: the cytoplasmic immunostaining for MMP9 is positive in isolated cells in the interstitium. The muscle cell cytoplasm is negative. (E) MMP9 in adult myocardium: cytoplasmic immunostaining for MMP9 in isolated cells in the interstitium; the muscle cells are negative. (F) CysC in fetal myocardium: We can see a more abundant cellularity than in the adult heart, with a less orderly arrangement of cells and slight cytoplasmic immunostaining of the cardiomyocytes for CysC. There are some small isolated cells in the interstitium that express cystatin in their cytoplasm. (G) CysC in adult myocardium: immunostained cardiomyocytes, with diffuse expression of CysC in the cytoplasm." ] ] ] "textoCompleto" => "BackgroundCystatin C (CysC) is a cysteine-rich protease inhibitor protein, which is widely distributed in human biologic fluids.<a class="elsevierStyleCrossRef" href="#bib0175">1</a> CysC has a low molecular weight and is formed by 120 amino acids in a single chain. It is synthesized as a preprotein and transmits a representative peptide signal of its extracellular function.<a class="elsevierStyleCrossRef" href="#bib0180">2</a> The gene that encodes CysC is located in chromosome 20<a class="elsevierStyleCrossRef" href="#bib0185">3</a> and belongs to the genes known as housekeeping genes. There is therefore no specific expression in any tissue, but rather its distribution is ubiquitous (kidneys, liver, pancreas, intestine, stomach, lung, placenta and seminal vesicles).<a class="elsevierStyleCrossRef" href="#bib0190">4</a> The principal physiological function of CysC is regulating the activity of extracellular cysteine proteases.<a class="elsevierStyleCrossRefs" href="#bib0195">5,6</a> Given its participation in the equilibrium between proteases and antiproteases, it has been suggested that CysC is involved in tissue remodeling,<a class="elsevierStyleCrossRef" href="#bib0205">7</a> atherosclerosis, aortic aneurysms<a class="elsevierStyleCrossRef" href="#bib0210">8</a> and left ventricular (LV) hypertrophy<a class="elsevierStyleCrossRef" href="#bib0215">9</a> and, as a result, in the pathogenesis of heart failure (HF).<a class="elsevierStyleCrossRefs" href="#bib0220">10,11</a>CysC behaves as a prognostic factor that is inversely related to the quality of aging<a class="elsevierStyleCrossRef" href="#bib0230">12</a> and directly related, in the general population, with the onset of cardiovascular events<a class="elsevierStyleCrossRef" href="#bib0235">13</a> and the incidence of HF.<a class="elsevierStyleCrossRefs" href="#bib0240">14–16</a> For individuals who already have HF, CysC is a robust prognostic marker of mortality, both in acute<a class="elsevierStyleCrossRefs" href="#bib0255">17–19</a> and chronic<a class="elsevierStyleCrossRef" href="#bib0270">20</a> HF, regardless of ejection fraction (EF).<a class="elsevierStyleCrossRef" href="#bib0275">21</a> It is not known whether the prognostic capacity of CysC is due to its involvement in ventricular remodeling, as suggested by Pate et al.,<a class="elsevierStyleCrossRef" href="#bib0220">10</a> or to its greater accuracy in calculating the glomerular filtration rate (GFR),<a class="elsevierStyleCrossRef" href="#bib0280">22</a> whose prognostic capacity in HF is well known.<a class="elsevierStyleCrossRef" href="#bib0285">23</a>This study is designed to analyze whether there are changes in CysC expression in the ventricular myocardium that are dependent on age and cardiovascular health. The study also analyzes whether plasma CysC concentrations have any relationship with the structural changes in the heart in already established HF.Patients and methodsWe studied 2 groups of unrelated patients.Analysis of CysC in myocardial tissueWe selected 9 myocardial tissue samples obtained from clinical autopsies (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), which were subjected to immunohistochemical staining for CysC, matrix metalloproteinase 9 (MMP9) and desmin.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The expression of housekeeping genes is very constant given that they encode proteins with essential functions for maintaining the life of the cell. Consequently, the synthesis and release of its protein products is altered in rare circumstances; for example, in the various stages of fetal development and in pathological disorders in adulthood in which they are directly involved. For this reason, the study included tissue cardiac samples from 4 fetuses of different gestational ages and from 5 adults whose autopsy showed that either they had no known structural heart disease (3 patients) or had heart disease (a patient with LV hypertrophy and thus pathological remodeling with no evidence of prior cardiac dysfunction and another with cardiogenic shock).To ensure that the tissue samples were viable for immunohistochemical analysis, we stained a forced expression protein (desmin) and another with putative expression related to cardiac remodeling (MMP9). For the immunohistochemical analysis, we employed the following commercial reagents: a monoclonal antibody (Clone D33, 1:100 solution) for desmin, a polyclonal antibody (ab3898, 1:100) for MMP9 (from Dako and Abcam [Cambridge, MA, United States of America]), respectively) and antibodies (Novus Biologicals, Cambridge, United Kingdom) for ICS (antibody 2C8).Analysis of the relationship between serum CysC concentration and heart structureWe analyzed a cohort of patients consecutively hospitalized for acute HF decompensation. Serum CysC concentrations were measured during the first 48h of hospitalization, and two-dimensional echocardiography was conducted. The patients were selected from the Department of Internal Medicine of University Clinic Hospital Lozano Blesa and gave their consent for participation in the study, which had been approved by the Ethics Committee of Aragon (PII10/038).HF exacerbation was defined as the gradual or rapid onset of signs and symptoms of HF that required unplanned hospitalization. The study included patients with de novo HF and chronic decompensated HF.<a class="elsevierStyleCrossRef" href="#bib0290">24</a> To ensure the diagnosis of HF, especially in patients with preserved EF, we only included those patients with serum concentrations of the amino-terminal fragment of the brain natriuretic peptide (NT-proBNP) higher than 900pg/mL.<a class="elsevierStyleCrossRef" href="#bib0295">25</a>Echocardiography was performed according to standard protocols<a class="elsevierStyleCrossRef" href="#bib0300">26</a> by an expert cardiologist who was blind to the patients’ clinical data and laboratory. The measurement of CysC and NT-proBNP was conducted in the Pathobiochemistry Laboratory of University Clinic Hospital Lozano Blesa with a BN ProSpec analyzer (Dade Behring GmbH, Liederbach, Germany) and a Modular Analytics E170 system (Roche Diagnostics GmbH, Mannheim, Germany), respectively, following the manufacturers’ specifications.Statistical analysisFor the qualitative variables, we measured the central tendency and dispersion (mean and standard deviation or median and interquartile range, according to whether the distribution was normal or not). For the bivariate analysis, we employed the chi-squared test; for the association analyses between qualitative variables, we applied Fisher's exact test. For the quantitative variables, we applied Student's t-test, the ANOVA test and the Mann–Whitney or Kruskal–Wallis test. For the correlations, we employed Spearman's test or Pearson's test if the distribution was normal. Values of p<0.05 were considered significant. We used the Statistical Package Social Sciences (SPSS 20.0) software for the analysis.ResultsMyocardial immunohistochemistry (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>)In contrast to the adult tissue samples, the fetal samples showed greater cell richness and a disordered structural pattern. The weak expression of desmin in the fetal myocardium is explained by a still early sarcomeric development stage (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, panel B). In the adult tissues, the desmin was positive in all samples, showing cross striations corresponding to intercalated discs (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, panel C). MMP9 showed similar immunostaining in the fetal (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, panel D) and adult samples (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, panel E). We found a number of interstitial cells that showed pigment uptake, but the staining was negative for MMP9. All cardiomyocytes, fetal (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, panel F) and adult (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, panel G), showed weak and diffuse staining for CysC, regardless of fetal age and patient health condition.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Relationship between serum CysC and heart structureWe studied 351 patients, 245 (70%) with HF and preserved EF (HFPEF) and 106 (30%) with HF and reduced EF (HFREF). The cohort's clinical characteristics are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>There was no significant correlation between CysC and the echocardiographic parameters (<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>). Although it was not one of the study objectives, we analyzed the prognostic information offered by serum CysC and its correlation with the estimated GFR by the 4-variable modification diet in renal diseases formula (MDRD-4). The CysC concentration had a direct correlation with all-cause mortality at 1 year and with the estimated GFR.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>DiscussionOur results show that CysC does not change its expression pattern in the ventricular myocardium during the various stages of fetal development or in adult patients according to their cardiovascular health. The immunohistochemical staining for CysC, weak and diffuse in all analyzed myocardial samples, suggests that this protease is synthesized constitutively and not induced and is secreted to the bloodstream. This pattern is consistent with the biological activities (mainly extracellular) of CysC.<a class="elsevierStyleCrossRefs" href="#bib0175">1,2</a> The fact that CysC staining in the ventricular myocardium of patients with LV hypertrophy or HF does not denote changes in distribution suggests that CysC is not involved in the progression of hypertension to HF. Although the assessed clinical cohort was not related to the patients from whom the tissue samples came, the absence of a correlation between the serum CysC concentrations and the heart structure should also be interpreted in this context. CysC is not related to cardiac morphological abnormalities (measured by echocardiography) in the final evolutionary stage of cardiac remodeling (i.e., in the presence of HF). However, CysC concentrations have an unquestionable prognostic value in HF.<a class="elsevierStyleCrossRefs" href="#bib0220">10,11,14–22</a> Due to its small molecular size and electrical charge, CysC is freely filtered in the glomerulus and is catabolized in the proximal convoluted tubule, without undergoing subsequent changes, which do occur with urea and creatinine.<a class="elsevierStyleCrossRef" href="#bib0225">11</a> For these reasons, CysC is particularly accurate when estimating GFR in renal dysfunction for clearances between 40 and 60mL/min, a range in which creatinine provides very inaccurate GFR values. In fact, CysC helps more accurately estimate the risk of death for patients with HF who have these GFR ranges.<a class="elsevierStyleCrossRefs" href="#bib0280">22,27</a>The possibility that CysC is involved in the early stages of cardiac remodeling was made evident by the results of the population cohort of the Dallas Heart Study.<a class="elsevierStyleCrossRef" href="#bib0220">10</a> The study used cardiac magnetic resonance on a population of 2548 unselected participants and found a linear relationship between serum concentrations of this protease, the thickness of the posterior LV wall and the ratio between the mass and end-diastolic volume of the LV, a new parameter the authors called cardiac “concentricity”. The authors suggest that CysC would be a useful parameter for identifying individuals with preclinical heart structure disorders, especially those with a specific phenotype of concentric LV hypertrophy, which, according to the authors’ hypothesis, would precede the onset of diastolic dysfunction or HF by years.<a class="elsevierStyleCrossRef" href="#bib0220">10</a> A number of studies have suggested that this phenotype of concentric LV hypertrophy depends on the equilibrium between cysteine-proteins (cathepsin B, S and K) and its inhibitors (CysC).<a class="elsevierStyleCrossRefs" href="#bib0215">9,28,29</a> However, our study found no changes in the staining pattern of myocardial CysC or between its serum concentrations and the echocardiographic parameters that would support this interpretation. These discrepancies could be partly explained by the differences in methodology and populations of the 2 studies. Although the study by Patel et al.<a class="elsevierStyleCrossRef" href="#bib0220">10</a> used an accurate technique such as magnetic resonance, it should be noted that remodeling is a local process and that serum CysC concentrations might not reflect what occurs in the tissue,<a class="elsevierStyleCrossRef" href="#bib0320">30</a> an assumption that is supported by our study's immunohistochemical results.The importance of equilibrium between proteases and antiproteases in the pathophysiology of cardiac remodeling has been previously studied.<a class="elsevierStyleCrossRef" href="#bib0325">31</a> A number of authors attribute a key role to the balance between matrix metalloproteinases and its inhibitors in the differentiation of phenotypes of HFPEF and HFREF.<a class="elsevierStyleCrossRef" href="#bib0330">32</a> Stypman et al.<a class="elsevierStyleCrossRef" href="#bib0310">28</a> analyzed the histology and histomorphometric changes in the hearts of 40 mice that lacked the coding gene for cathepsin L. After 1 year, the deficient mice showed significant growth (compared with controls) of the atrium and ventricle, secondary to myocardial interstitial fibrosis. These abnormalities are reflected in the echocardiography as a significant impairment in LV contractility, interpreted as an adaptive response to histological changes experienced by the cathepsin L-deficient mouse.<a class="elsevierStyleCrossRef" href="#bib0310">28</a> An increase has also been encountered in cathepsin B expression, both in the messenger RNA and the protein, in a group of 20 patients with severe dilated cardiomyopathy, when compared with 5 heart donors.<a class="elsevierStyleCrossRef" href="#bib0315">29</a> Therefore, there is evidence that some lysosomal proteases participate in cardiac remodeling; however, the antiprotease's role was not analyzed in these studies.In any case, there are numerous families of proteases and antiproteases, and their physiological roles vary. The behavior of some of them might therefore not be extrapolatable. Cheng et al.,<a class="elsevierStyleCrossRef" href="#bib0215">9</a> using real-time polymerase chain reaction, immunoblot and immunohistochemistry, analyzed the expression of cathepsin S and K and its antiprotease (CysC) in hypertrophic human and murine hearts. The authors found that cathepsin expression was greater in the hearts of individuals with HF than in those who only had LV hypertrophy and those in the control group. CysC expression, however, did not increase in any tissue specimen from the analyzed individuals.<a class="elsevierStyleCrossRef" href="#bib0215">9</a> These results agree with those we found in the present study. There are a number of explanations that justify the lack of CysC expression in ventricular remodeling. First, it could be that CysC secretion in response to the increase in cathepsin production is deficient. In this case, the absence of CysC action would lead to increased elastolytic activity by the cathepsins, which would indirectly promote ventricular dilation and HF. Second, it is possible that certain local factors are essential in the location of CysC activity. It is known that a neutral extracellular pH reduces cathepsin activity, and it has been shown that lysosomal enzyme H+-ATPase translocates to the membrane<a class="elsevierStyleCrossRef" href="#bib0335">33</a> and creates an acid environment that promotes the activation of the cathepsin activator of matrix metalloproteinases.<a class="elsevierStyleCrossRef" href="#bib0340">34</a> It is possible that something similar occurs with CysC. In fact, this protease exerts its physiological actions on the bodily fluids, far from the cells that produce it.<a class="elsevierStyleCrossRef" href="#bib0180">2</a>Our study has a number of limitations. The number of tissue samples studied was small, and the immunohistochemical staining, in addition to being a qualitative method, might not reflect in a sufficiently sensitive manner what occurs at the tissue level in complex and dynamic biological processes.In conclusion, the weak and homogeneous distribution pattern of the immunohistochemistry staining for CysC in the myocardium of fetuses of various ages and of adults with and without heart disease, as well as, indirectly, the lack of relationship between serum CysC concentrations and the morphological and functional parameters measured by echocardiography in patients with HF add an element of discussion to the unconcluded debate on the role of CysC in cardiac remodeling. Our results suggest that CysC is not directly involved in cardiac remodeling that leads to HF.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres611115" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0005" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec625104" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres611116" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0025" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec625105" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Analysis of CysC in myocardial tissue" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Analysis of the relationship between serum CysC concentration and heart structure" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Myocardial immunohistochemistry (Fig. 1)" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Relationship between serum CysC and heart structure" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-08-30" "fechaAceptado" => "2015-11-01" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec625104" "palabras" => array:5 [ 0 => "Cystatin C" 1 => "Heart failure" 2 => "Ventricular remodeling" 3 => "Housekeeping genes" 4 => "Cystein proteases" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec625105" "palabras" => array:5 [ 0 => "Cistatina C" 1 => "Insuficiencia cardiaca" 2 => "Remodelado ventricular" 3 => "Genes de mantenimiento" 4 => "Cisteín proteasas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Cystatin C (CysC) is a protease encoded by housekeeping genes. Although its prognostic value in heart failure (HF) is well known, it is debatable whether this value is due to the greater accuracy of CysC in calculating the glomerular filtration rate or to its involvement in pathological ventricular remodeling. The aim of this study was to determine whether CysC expression changes in the myocardium of fetuses of different ages and in the myocardium of adults with various cardiovascular diseases, as well as to analyze the correlation between its serum concentrations and cardiac structure and morphology in a patient group with HF. Patients and methodsWe analyzed the correlations (Pearson's r and Spearman's test) between the serum CysC levels and echocardiographic parameters of 351 patients with HF. We also performed immunohistochemical staining for CysC, metalloproteinase-9 (MMP-9) and desmin in 9 cardiac tissue samples from autopsies of 4 fetuses of different gestational ages and 5 healthy adults or adults with cardiovascular disease. ResultsFor the patients with HF, there was no correlation between the CysC concentrations and the cardiac parameters measured by 2D echocardiography. The immunohistochemistry showed a weak background staining for CysC in all samples, regardless of age and the presence or absence of cardiovascular diseases. ConclusionsOur results suggest that CysC does not have a significant role in the pathological remodeling of the left ventricle in HF." "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0005" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "La cistatina C (CisC) es una proteasa codificada por genes de mantenimiento («housekeeping genes»). Aunque su valor pronóstico en la insuficiencia cardiaca (IC) es bien conocido, se debate si es debido a su mayor precisión en la estimación del filtrado glomerular, o a su implicación en el remodelado ventricular patológico. El propósito de este estudio fue comprobar si la expresión de CisC se modificaba en el miocardio de fetos de diferentes edades y en el de adultos con diversas enfermedades cardiovasculares, así como analizar la correlación entre sus concentraciones séricas y la estructura y morfología cardiaca en un grupo de pacientes con IC. Pacientes y métodosSe analizaron las correlaciones (test de Pearson y Spearman) entre la CisC sérica y los parámetros ecocardiográficos de 351 pacientes con IC. También se realizó una tinción inmunohistoquímica para CisC, metaloproteinasa 9 (MMP-9) y desmina en 9 muestras de tejido cardiaco procedentes de las autopsias de 4 fetos con diferente edad gestacional y 5 adultos sanos o con enfermedad cardiovascular. ResultadosEn pacientes con IC no se encontró correlación entre las concentraciones de CisC y los parámetros cardiacos medidos por ecocardiografía 2 D. La inmunohistoquímica mostró una débil tinción de fondo para CisC en todas las muestras, independientemente de la edad y la presencia o no de enfermedades cardiovasculares. ConclusionesNuestros resultados sugieren que la CisC no tiene un papel significativo en el remodelado patológico del ventrículo izquierdo en la IC." "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0025" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Pérez-Calvo JI, Castiella Muruzábal T, Búcar Barjud M, Josa Laorden C, Sánchez Marteles M, Lacambra Blasco I, et al. Ausencia de implicación de la cistatina C en el remodelado ventricular y la insuficiencia cardiaca. Rev Clin Esp. 2016;216:55–61." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1415 "Ancho" => 1955 "Tamanyo" => 561871 ] ] "descripcion" => array:1 [ "en" => "Immunohistochemistry staining of myocardial tissue samples (20×). (A) Contrast hematoxylin and antibody diluent (check-up). We can see cardiac myocytes with normal structures and weakly stained nuclei occupying a central position within the cells, with background hematoxylin staining. We can also see lipofuscin pigment in the poles of the nucleus (Ab 20×). (B) Desmin in fetal myocardium: desmin expression is much weaker than in the adult heart or is negative, which likely translates into a lack of development of the sarcomeres. (C) Desmin in adult myocardium: cross striations throughout the myocardium; the intercalated bands show up as darker. (D) MMP9 in fetal myocardium: the cytoplasmic immunostaining for MMP9 is positive in isolated cells in the interstitium. The muscle cell cytoplasm is negative. (E) MMP9 in adult myocardium: cytoplasmic immunostaining for MMP9 in isolated cells in the interstitium; the muscle cells are negative. (F) CysC in fetal myocardium: We can see a more abundant cellularity than in the adult heart, with a less orderly arrangement of cells and slight cytoplasmic immunostaining of the cardiomyocytes for CysC. There are some small isolated cells in the interstitium that express cystatin in their cytoplasm. (G) CysC in adult myocardium: immunostained cardiomyocytes, with diffuse expression of CysC in the cytoplasm." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Abbreviations: AMI, acute myocardial infarction; LV, left ventricle." "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Fetal samples \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adult samples \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 20 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50-Year-old woman with healthy heart (check-up) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 22 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">71-Year-old man with healthy heart (check-up) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 30 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">84-Year-old man with healthy heart(check-up) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 33 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">53-Year-old man with LV hypertrophy secondary to arterial hypertension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80-Year-old man with cardiogenic shock due to AMI \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001133.png" ] ] ] ] "descripcion" => array:1 [ "en" => "General characteristics of the myocardial samples." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; HFREF, heart failure with reduced ejection fraction; MDRD, modification diet in renal disease formula based on 4 parameters; NT-proBNP, amino-terminal fragment of the brain natriuretic propeptide; NYHA, New York Heart Association.The values are expressed as mean (standard deviation) or number (percentage) as necessary." "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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical cohort (n=351) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HFREF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">106 (30.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age, y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78.41 (6.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">170 (48.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BMI, kg/m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29.86 (10.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Etiology</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">157 (44.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ischemic heart disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">80 (22.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Others<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">114 (32.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">NYHA functional class</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">37 (10.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">189 (53.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">119 (33.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (1.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Comorbidity</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Arterial hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">255 (72.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Atrial fibrillation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">205 (58.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diabetes mellitus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">136 (38.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">COPD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">71 (20.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sodium, mEq/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">141.7 (4.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hemoglobin, g/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.12 (0.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">eGFR, mL/min/1.73m2 (MDRD-4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52.16 (21.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cystatin, mg/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.5 (0.55) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NT-proBNP, pg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6183 (9575) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001134.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Some patients can have several simultaneous etiologies." ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics of the clinical cohort." ] ] 3 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Abbreviations: LV, left ventricle; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter." "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="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">n \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Media (DE) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Correlation with CysC</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">R<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LV ejection fraction, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">348 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51.75 (13.81) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.071 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.197 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Left atrium diameter, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">272 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47.77 (9.26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.082 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.179 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVEDD, mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">268 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55.24 (9.62) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.844 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVESD, mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">263 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38.47 (11.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.033 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.599 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Septum thickness, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">271 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.53 (2.21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.101 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.099 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posterior wall, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">268 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.43 (2.03) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.928 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Left ventricular mass, g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">265 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">205.61 (82) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.903 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indexed LV mass, g/m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">265 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">118.85 (45.35) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.856 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">“Concentricity”<a class="elsevierStyleCrossRef" href="#tblfn0015">**</a>, g/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">265 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.68 (1.16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.081 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.197 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E-wave, m/s) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">200 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.99 (0.36) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.325 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">A-wave<a class="elsevierStyleCrossRef" href="#tblfn0015">**</a>, m/s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.82 (0.33) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.117 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.340 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E/A ratio<a class="elsevierStyleCrossRef" href="#tblfn0020">***</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.25 (0.75) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.907 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pulmonary artery systolic pressure, mm Hg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">115 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46.5 (16.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.063 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.509 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001136.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "*" "nota" => "Spearman's rho." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "**" "nota" => "“Concentricity”, ratio of LV mass to LVEDD." ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "***" "nota" => "Only for patients in sinus rhythm." ] ] ] "descripcion" => array:1 [ "en" => "Echocardiographic parameters (clinical cohort) and correlation with serum CysC concentrations." ] ] 4 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Abbreviations: LA, left atrium; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; sPAP, systolic pulmonary artery pressure." "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="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Full cohort \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q1≤1.1mg/dL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q21.11–1.35mg/dL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q31.36–1.75mg/dL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q4>1.75mg/dL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVEF, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51.7 (13.95) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50.55 (13.48) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52.65 (14.17) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49.07 (14.78) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54.77 (12.82) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.075 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LA diameter, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47.74 (9.27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48.36 (9.14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47.95 (8.78) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47.38 (10.21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47.31 (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVEDV, mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55.25 (9.64) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54.43 (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.36 (9.12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56.56 (9.84) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.61 (8.39) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.204 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVESV, mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38.51 (11.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38.8 (12.43) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 (10.97) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39.45 (11.76) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36.9 (9.66) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.57 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Septum thickness, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.52 (2.21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.18 (2.71) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.66 (2.02) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.56 (2.08) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.68 (1.99) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.539 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posterior wall thickness, mm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.42 (2.03) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.47 (2.77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.38 (1.85) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.49 (1.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.35 (1.62) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.971 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LV mass, g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">204.09 (82.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">198.33 (91.28) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">206.48 (82.76) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">213.71 (86.05) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">197.32 (70.76) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.628 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LV mass index, g/m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">115.5 (43) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">114.2 (48.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">115 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">121.7 (45.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">111.2 (36.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.56 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">“Concentricity”<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a>, g/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.66 (1.15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.64 (1.46) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.67 (1.16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.72 (1.04) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.63 (0.96) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.97 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E-wave \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.99 (0.36) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.97 (0.34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.97 (0.26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.98 (0.43) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.04 (0.36) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.786 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">A-wave<a class="elsevierStyleCrossRef" href="#tblfn0030">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.82 (0.33) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.81 (0.28) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.72 (0.27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.91 (0.38) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.83 (0.33) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.378 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E/A<a class="elsevierStyleCrossRef" href="#tblfn0030">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.25 (0.75) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.37 (1.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.28 (0.55) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.03 (0.53) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.37 (0.79) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.342 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">sPAP, mm Hg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46.6 (16.44) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45.81 (13.51) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42.14 (14.51) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48.81 (21.27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48.03 (15.71) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.504 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001135.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "*" "nota" => "“Concentricity”: LV mass/LV diastolic diameter." ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "**" "nota" => "Only for patients in sinus rhythm. 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Original article

Absence of cystatin C involvement in ventricular remodelling and heart failure

Ausencia de implicación de la cistatina C en el remodelado ventricular y la insuficiencia cardiaca

J.I. Pérez-Calvoa,

Corresponding author

jiperez@unizar.es

Corresponding author.

, T. Castiella Muruzábalb, M. Búcar Barjudc, C. Josa Laordenc, M. Sánchez Martelesc, I. Lacambra Blascod, M.C. Asensio Lópeze, D.A. Pascual Figale

a Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa Facultad de Medicina, Instituto de investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain

b Servicio de Anatomía Patológica, Hospital Clínico Universitario Lozano Blesa Facultad de Medicina, Zaragoza, Spain

c Servicio de Medicina Interna, Hospital Clínico Universitario Lozano Blesa, Instituto de investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain

d Servicio de Cardiología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

e Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca Facultad de Medicina, Murcia, Spain

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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Immunohistochemistry staining of myocardial tissue samples &#40;20&#215;&#41;&#46; &#40;A&#41; Contrast hematoxylin and antibody diluent &#40;check-up&#41;&#46; We can see cardiac myocytes with normal structures and weakly stained nuclei occupying a central position within the cells&#44; with background hematoxylin staining&#46; We can also see lipofuscin pigment in the poles of the nucleus &#40;Ab 20&#215;&#41;&#46; &#40;B&#41; Desmin in fetal myocardium&#58; desmin expression is much weaker than in the adult heart or is negative&#44; which likely translates into a lack of development of the sarcomeres&#46; &#40;C&#41; Desmin in adult myocardium&#58; cross striations throughout the myocardium&#59; the intercalated bands show up as darker&#46; &#40;D&#41; MMP9 in fetal myocardium&#58; the cytoplasmic immunostaining for MMP9 is positive in isolated cells in the interstitium&#46; The muscle cell cytoplasm is negative&#46; &#40;E&#41; MMP9 in adult myocardium&#58; cytoplasmic immunostaining for MMP9 in isolated cells in the interstitium&#59; the muscle cells are negative&#46; &#40;F&#41; CysC in fetal myocardium&#58; We can see a more abundant cellularity than in the adult heart&#44; with a less orderly arrangement of cells and slight cytoplasmic immunostaining of the cardiomyocytes for CysC&#46; There are some small isolated cells in the interstitium that express cystatin in their cytoplasm&#46; &#40;G&#41; CysC in adult myocardium&#58; immunostained cardiomyocytes&#44; with diffuse expression of CysC in the cytoplasm&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cystatin C &#40;CysC&#41; is a cysteine-rich protease inhibitor protein&#44; which is widely distributed in human biologic fluids&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> CysC has a low molecular weight and is formed by 120 amino acids in a single chain&#46; It is synthesized as a preprotein and transmits a representative peptide signal of its extracellular function&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> The gene that encodes CysC is located in chromosome 20<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> and belongs to the genes known as housekeeping genes&#46; There is therefore no specific expression in any tissue&#44; but rather its distribution is ubiquitous &#40;kidneys&#44; liver&#44; pancreas&#44; intestine&#44; stomach&#44; lung&#44; placenta and seminal vesicles&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> The principal physiological function of CysC is regulating the activity of extracellular cysteine proteases&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6</span></a> Given its participation in the equilibrium between proteases and antiproteases&#44; it has been suggested that CysC is involved in tissue remodeling&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a> atherosclerosis&#44; aortic aneurysms<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> and left ventricular &#40;LV&#41; hypertrophy<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> and&#44; as a result&#44; in the pathogenesis of heart failure &#40;HF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">CysC behaves as a prognostic factor that is inversely related to the quality of aging<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> and directly related&#44; in the general population&#44; with the onset of cardiovascular events<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> and the incidence of HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#8211;16</span></a> For individuals who already have HF&#44; CysC is a robust prognostic marker of mortality&#44; both in acute<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">17&#8211;19</span></a> and chronic<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> HF&#44; regardless of ejection fraction &#40;EF&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> It is not known whether the prognostic capacity of CysC is due to its involvement in ventricular remodeling&#44; as suggested by Pate et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> or to its greater accuracy in calculating the glomerular filtration rate &#40;GFR&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> whose prognostic capacity in HF is well known&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">This study is designed to analyze whether there are changes in CysC expression in the ventricular myocardium that are dependent on age and cardiovascular health&#46; The study also analyzes whether plasma CysC concentrations have any relationship with the structural changes in the heart in already established HF&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Patients and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">We studied 2 groups of unrelated patients&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Analysis of CysC in myocardial tissue</span><p id="par0025" class="elsevierStylePara elsevierViewall">We selected 9 myocardial tissue samples obtained from clinical autopsies &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; which were subjected to immunohistochemical staining for CysC&#44; matrix metalloproteinase 9 &#40;MMP9&#41; and desmin&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The expression of housekeeping genes is very constant given that they encode proteins with essential functions for maintaining the life of the cell&#46; Consequently&#44; the synthesis and release of its protein products is altered in rare circumstances&#59; for example&#44; in the various stages of fetal development and in pathological disorders in adulthood in which they are directly involved&#46; For this reason&#44; the study included tissue cardiac samples from 4 fetuses of different gestational ages and from 5 adults whose autopsy showed that either they had no known structural heart disease &#40;3 patients&#41; or had heart disease &#40;a patient with LV hypertrophy and thus pathological remodeling with no evidence of prior cardiac dysfunction and another with cardiogenic shock&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">To ensure that the tissue samples were viable for immunohistochemical analysis&#44; we stained a forced expression protein &#40;desmin&#41; and another with putative expression related to cardiac remodeling &#40;MMP9&#41;&#46; For the immunohistochemical analysis&#44; we employed the following commercial reagents&#58; a monoclonal antibody &#40;Clone D33&#44; 1&#58;100 solution&#41; for desmin&#44; a polyclonal antibody &#40;ab3898&#44; 1&#58;100&#41; for MMP9 &#40;from Dako and Abcam &#91;Cambridge&#44; MA&#44; United States of America&#93;&#41;&#44; respectively&#41; and antibodies &#40;Novus Biologicals&#44; Cambridge&#44; United Kingdom&#41; for ICS &#40;antibody 2C8&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Analysis of the relationship between serum CysC concentration and heart structure</span><p id="par0040" class="elsevierStylePara elsevierViewall">We analyzed a cohort of patients consecutively hospitalized for acute HF decompensation&#46; Serum CysC concentrations were measured during the first 48<span class="elsevierStyleHsp" style=""></span>h of hospitalization&#44; and two-dimensional echocardiography was conducted&#46; The patients were selected from the Department of Internal Medicine of University Clinic Hospital Lozano Blesa and gave their consent for participation in the study&#44; which had been approved by the Ethics Committee of Aragon &#40;PII10&#47;038&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">HF exacerbation was defined as the gradual or rapid onset of signs and symptoms of HF that required unplanned hospitalization&#46; The study included patients with <span class="elsevierStyleItalic">de novo</span> HF and chronic decompensated HF&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a> To ensure the diagnosis of HF&#44; especially in patients with preserved EF&#44; we only included those patients with serum concentrations of the amino-terminal fragment of the brain natriuretic peptide &#40;NT-proBNP&#41; higher than 900<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Echocardiography was performed according to standard protocols<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> by an expert cardiologist who was blind to the patients&#8217; clinical data and laboratory&#46; The measurement of CysC and NT-proBNP was conducted in the Pathobiochemistry Laboratory of University Clinic Hospital Lozano Blesa with a BN ProSpec analyzer &#40;Dade Behring GmbH&#44; Liederbach&#44; Germany&#41; and a Modular Analytics E170 system &#40;Roche Diagnostics GmbH&#44; Mannheim&#44; Germany&#41;&#44; respectively&#44; following the manufacturers&#8217; specifications&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">For the qualitative variables&#44; we measured the central tendency and dispersion &#40;mean and standard deviation or median and interquartile range&#44; according to whether the distribution was normal or not&#41;&#46; For the bivariate analysis&#44; we employed the chi-squared test&#59; for the association analyses between qualitative variables&#44; we applied Fisher&#39;s exact test&#46; For the quantitative variables&#44; we applied Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#44; the ANOVA test and the Mann&#8211;Whitney or Kruskal&#8211;Wallis test&#46; For the correlations&#44; we employed Spearman&#39;s test or Pearson&#39;s test if the distribution was normal&#46; Values of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;0&#46;05 were considered significant&#46; We used the Statistical Package Social Sciences &#40;SPSS 20&#46;0&#41; software for the analysis&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Myocardial immunohistochemistry &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;</span><p id="par0060" class="elsevierStylePara elsevierViewall">In contrast to the adult tissue samples&#44; the fetal samples showed greater cell richness and a disordered structural pattern&#46; The weak expression of desmin in the fetal myocardium is explained by a still early sarcomeric development stage &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; panel B&#41;&#46; In the adult tissues&#44; the desmin was positive in all samples&#44; showing cross striations corresponding to intercalated discs &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; panel C&#41;&#46; MMP9 showed similar immunostaining in the fetal &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; panel D&#41; and adult samples &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; panel E&#41;&#46; We found a number of interstitial cells that showed pigment uptake&#44; but the staining was negative for MMP9&#46; All cardiomyocytes&#44; fetal &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; panel F&#41; and adult &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; panel G&#41;&#44; showed weak and diffuse staining for CysC&#44; regardless of fetal age and patient health condition&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Relationship between serum CysC and heart structure</span><p id="par0065" class="elsevierStylePara elsevierViewall">We studied 351 patients&#44; 245 &#40;70&#37;&#41; with HF and preserved EF &#40;HFPEF&#41; and 106 &#40;30&#37;&#41; with HF and reduced EF &#40;HFREF&#41;&#46; The cohort&#39;s clinical characteristics are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">There was no significant correlation between CysC and the echocardiographic parameters &#40;<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>&#41;&#46; Although it was not one of the study objectives&#44; we analyzed the prognostic information offered by serum CysC and its correlation with the estimated GFR by the 4-variable modification diet in renal diseases formula &#40;MDRD-4&#41;&#46; The CysC concentration had a direct correlation with all-cause mortality at 1 year and with the estimated GFR&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Our results show that CysC does not change its expression pattern in the ventricular myocardium during the various stages of fetal development or in adult patients according to their cardiovascular health&#46; The immunohistochemical staining for CysC&#44; weak and diffuse in all analyzed myocardial samples&#44; suggests that this protease is synthesized constitutively and not induced and is secreted to the bloodstream&#46; This pattern is consistent with the biological activities &#40;mainly extracellular&#41; of CysC&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#44;2</span></a> The fact that CysC staining in the ventricular myocardium of patients with LV hypertrophy or HF does not denote changes in distribution suggests that CysC is not involved in the progression of hypertension to HF&#46; Although the assessed clinical cohort was not related to the patients from whom the tissue samples came&#44; the absence of a correlation between the serum CysC concentrations and the heart structure should also be interpreted in this context&#46; CysC is not related to cardiac morphological abnormalities &#40;measured by echocardiography&#41; in the final evolutionary stage of cardiac remodeling &#40;i&#46;e&#46;&#44; in the presence of HF&#41;&#46; However&#44; CysC concentrations have an unquestionable prognostic value in HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">10&#44;11&#44;14&#8211;22</span></a> Due to its small molecular size and electrical charge&#44; CysC is freely filtered in the glomerulus and is catabolized in the proximal convoluted tubule&#44; without undergoing subsequent changes&#44; which do occur with urea and creatinine&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> For these reasons&#44; CysC is particularly accurate when estimating GFR in renal dysfunction for clearances between 40 and 60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; a range in which creatinine provides very inaccurate GFR values&#46; In fact&#44; CysC helps more accurately estimate the risk of death for patients with HF who have these GFR ranges&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">22&#44;27</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The possibility that CysC is involved in the early stages of cardiac remodeling was made evident by the results of the population cohort of the Dallas Heart Study&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> The study used cardiac magnetic resonance on a population of 2548 unselected participants and found a linear relationship between serum concentrations of this protease&#44; the thickness of the posterior LV wall and the ratio between the mass and end-diastolic volume of the LV&#44; a new parameter the authors called cardiac &#8220;concentricity&#8221;&#46; The authors suggest that CysC would be a useful parameter for identifying individuals with preclinical heart structure disorders&#44; especially those with a specific phenotype of concentric LV hypertrophy&#44; which&#44; according to the authors&#8217; hypothesis&#44; would precede the onset of diastolic dysfunction or HF by years&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> A number of studies have suggested that this phenotype of concentric LV hypertrophy depends on the equilibrium between cysteine-proteins &#40;cathepsin B&#44; S and K&#41; and its inhibitors &#40;CysC&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#44;28&#44;29</span></a> However&#44; our study found no changes in the staining pattern of myocardial CysC or between its serum concentrations and the echocardiographic parameters that would support this interpretation&#46; These discrepancies could be partly explained by the differences in methodology and populations of the 2 studies&#46; Although the study by Patel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> used an accurate technique such as magnetic resonance&#44; it should be noted that remodeling is a local process and that serum CysC concentrations might not reflect what occurs in the tissue&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> an assumption that is supported by our study&#39;s immunohistochemical results&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The importance of equilibrium between proteases and antiproteases in the pathophysiology of cardiac remodeling has been previously studied&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> A number of authors attribute a key role to the balance between matrix metalloproteinases and its inhibitors in the differentiation of phenotypes of HFPEF and HFREF&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a> Stypman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> analyzed the histology and histomorphometric changes in the hearts of 40 mice that lacked the coding gene for cathepsin L&#46; After 1 year&#44; the deficient mice showed significant growth &#40;compared with controls&#41; of the atrium and ventricle&#44; secondary to myocardial interstitial fibrosis&#46; These abnormalities are reflected in the echocardiography as a significant impairment in LV contractility&#44; interpreted as an adaptive response to histological changes experienced by the cathepsin L-deficient mouse&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> An increase has also been encountered in cathepsin B expression&#44; both in the messenger RNA and the protein&#44; in a group of 20 patients with severe dilated cardiomyopathy&#44; when compared with 5 heart donors&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> Therefore&#44; there is evidence that some lysosomal proteases participate in cardiac remodeling&#59; however&#44; the antiprotease&#39;s role was not analyzed in these studies&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In any case&#44; there are numerous families of proteases and antiproteases&#44; and their physiological roles vary&#46; The behavior of some of them might therefore not be extrapolatable&#46; Cheng et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> using real-time polymerase chain reaction&#44; immunoblot and immunohistochemistry&#44; analyzed the expression of cathepsin S and K and its antiprotease &#40;CysC&#41; in hypertrophic human and murine hearts&#46; The authors found that cathepsin expression was greater in the hearts of individuals with HF than in those who only had LV hypertrophy and those in the control group&#46; CysC expression&#44; however&#44; did not increase in any tissue specimen from the analyzed individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> These results agree with those we found in the present study&#46; There are a number of explanations that justify the lack of CysC expression in ventricular remodeling&#46; First&#44; it could be that CysC secretion in response to the increase in cathepsin production is deficient&#46; In this case&#44; the absence of CysC action would lead to increased elastolytic activity by the cathepsins&#44; which would indirectly promote ventricular dilation and HF&#46; Second&#44; it is possible that certain local factors are essential in the location of CysC activity&#46; It is known that a neutral extracellular pH reduces cathepsin activity&#44; and it has been shown that lysosomal enzyme H<span class="elsevierStyleSup">&#43;</span>-ATPase translocates to the membrane<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> and creates an acid environment that promotes the activation of the cathepsin activator of matrix metalloproteinases&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a> It is possible that something similar occurs with CysC&#46; In fact&#44; this protease exerts its physiological actions on the bodily fluids&#44; far from the cells that produce it&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Our study has a number of limitations&#46; The number of tissue samples studied was small&#44; and the immunohistochemical staining&#44; in addition to being a qualitative method&#44; might not reflect in a sufficiently sensitive manner what occurs at the tissue level in complex and dynamic biological processes&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In conclusion&#44; the weak and homogeneous distribution pattern of the immunohistochemistry staining for CysC in the myocardium of fetuses of various ages and of adults with and without heart disease&#44; as well as&#44; indirectly&#44; the lack of relationship between serum CysC concentrations and the morphological and functional parameters measured by echocardiography in patients with HF add an element of discussion to the unconcluded debate on the role of CysC in cardiac remodeling&#46; Our results suggest that CysC is not directly involved in cardiac remodeling that leads to HF&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Myocardial immunohistochemistry &#40;Fig&#46; 1&#41;"
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              "titulo" => "Relationship between serum CysC and heart structure"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cystatin C &#40;CysC&#41; is a protease encoded by housekeeping genes&#46; Although its prognostic value in heart failure &#40;HF&#41; is well known&#44; it is debatable whether this value is due to the greater accuracy of CysC in calculating the glomerular filtration rate or to its involvement in pathological ventricular remodeling&#46; The aim of this study was to determine whether CysC expression changes in the myocardium of fetuses of different ages and in the myocardium of adults with various cardiovascular diseases&#44; as well as to analyze the correlation between its serum concentrations and cardiac structure and morphology in a patient group with HF&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We analyzed the correlations &#40;Pearson&#39;s <span class="elsevierStyleItalic">r</span> and Spearman&#39;s test&#41; between the serum CysC levels and echocardiographic parameters of 351 patients with HF&#46; We also performed immunohistochemical staining for CysC&#44; metalloproteinase-9 &#40;MMP-9&#41; and desmin in 9 cardiac tissue samples from autopsies of 4 fetuses of different gestational ages and 5 healthy adults or adults with cardiovascular disease&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">For the patients with HF&#44; there was no correlation between the CysC concentrations and the cardiac parameters measured by 2D echocardiography&#46; The immunohistochemistry showed a weak background staining for CysC in all samples&#44; regardless of age and the presence or absence of cardiovascular diseases&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our results suggest that CysC does not have a significant role in the pathological remodeling of the left ventricle in HF&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La cistatina C &#40;CisC&#41; es una proteasa codificada por genes de mantenimiento &#40;&#171;<span class="elsevierStyleItalic">housekeeping genes&#187;</span>&#41;&#46; Aunque su valor pron&#243;stico en la insuficiencia cardiaca &#40;IC&#41; es bien conocido&#44; se debate si es debido a su mayor precisi&#243;n en la estimaci&#243;n del filtrado glomerular&#44; o a su implicaci&#243;n en el remodelado ventricular patol&#243;gico&#46; El prop&#243;sito de este estudio fue comprobar si la expresi&#243;n de CisC se modificaba en el miocardio de fetos de diferentes edades y en el de adultos con diversas enfermedades cardiovasculares&#44; as&#237; como analizar la correlaci&#243;n entre sus concentraciones s&#233;ricas y la estructura y morfolog&#237;a cardiaca en un grupo de pacientes con IC&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se analizaron las correlaciones &#40;test de Pearson y Spearman&#41; entre la CisC s&#233;rica y los par&#225;metros ecocardiogr&#225;ficos de 351 pacientes con IC&#46; Tambi&#233;n se realiz&#243; una tinci&#243;n inmunohistoqu&#237;mica para CisC&#44; metaloproteinasa 9 &#40;MMP-9&#41; y desmina en 9 muestras de tejido cardiaco procedentes de las autopsias de 4 fetos con diferente edad gestacional y 5 adultos sanos o con enfermedad cardiovascular&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En pacientes con IC no se encontr&#243; correlaci&#243;n entre las concentraciones de CisC y los par&#225;metros cardiacos medidos por ecocardiograf&#237;a 2 D&#46; La inmunohistoqu&#237;mica mostr&#243; una d&#233;bil tinci&#243;n de fondo para CisC en todas las muestras&#44; independientemente de la edad y la presencia o no de enfermedades cardiovasculares&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados sugieren que la CisC no tiene un papel significativo en el remodelado patol&#243;gico del ventr&#237;culo izquierdo en la IC&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:1 [
            "identificador" => "abst0025"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Pacientes y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; P&#233;rez-Calvo JI&#44; Castiella Muruz&#225;bal T&#44; B&#250;car Barjud M&#44; Josa Laorden C&#44; S&#225;nchez Marteles M&#44; Lacambra Blasco I&#44; et al&#46; Ausencia de implicaci&#243;n de la cistatina C en el remodelado ventricular y la insuficiencia cardiaca&#46; Rev Clin Esp&#46; 2016&#59;216&#58;55&#8211;61&#46;</p>"
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1415
            "Ancho" => 1955
            "Tamanyo" => 561871
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Immunohistochemistry staining of myocardial tissue samples &#40;20&#215;&#41;&#46; &#40;A&#41; Contrast hematoxylin and antibody diluent &#40;check-up&#41;&#46; We can see cardiac myocytes with normal structures and weakly stained nuclei occupying a central position within the cells&#44; with background hematoxylin staining&#46; We can also see lipofuscin pigment in the poles of the nucleus &#40;Ab 20&#215;&#41;&#46; &#40;B&#41; Desmin in fetal myocardium&#58; desmin expression is much weaker than in the adult heart or is negative&#44; which likely translates into a lack of development of the sarcomeres&#46; &#40;C&#41; Desmin in adult myocardium&#58; cross striations throughout the myocardium&#59; the intercalated bands show up as darker&#46; &#40;D&#41; MMP9 in fetal myocardium&#58; the cytoplasmic immunostaining for MMP9 is positive in isolated cells in the interstitium&#46; The muscle cell cytoplasm is negative&#46; &#40;E&#41; MMP9 in adult myocardium&#58; cytoplasmic immunostaining for MMP9 in isolated cells in the interstitium&#59; the muscle cells are negative&#46; &#40;F&#41; CysC in fetal myocardium&#58; We can see a more abundant cellularity than in the adult heart&#44; with a less orderly arrangement of cells and slight cytoplasmic immunostaining of the cardiomyocytes for CysC&#46; There are some small isolated cells in the interstitium that express cystatin in their cytoplasm&#46; &#40;G&#41; CysC in adult myocardium&#58; immunostained cardiomyocytes&#44; with diffuse expression of CysC in the cytoplasm&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; AMI&#44; acute myocardial infarction&#59; LV&#44; left ventricle&#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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Fetal samples&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adult samples&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 20 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50-Year-old woman with healthy heart &#40;check-up&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 22 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">71-Year-old man with healthy heart &#40;check-up&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 30 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">84-Year-old man with healthy heart&#40;check-up&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gestational age 33 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53-Year-old man with LV hypertrophy secondary to arterial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80-Year-old man with cardiogenic shock due to AMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1001133.png"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">General characteristics of the myocardial samples&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; BMI&#44; body mass index&#59; COPD&#44; chronic obstructive pulmonary disease&#59; eGFR&#44; estimated glomerular filtration rate&#59; HFREF&#44; heart failure with reduced ejection fraction&#59; MDRD&#44; modification diet in renal disease formula based on 4 parameters&#59; NT-proBNP&#44; amino-terminal fragment of the brain natriuretic propeptide&#59; NYHA&#44; New York Heart Association&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">The values are expressed as mean &#40;standard deviation&#41; or number &#40;percentage&#41; as necessary&#46;</p>"
          "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="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical cohort &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>351&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">HFREF</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">106 &#40;30&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age&#44; y</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78&#46;41 &#40;6&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Male sex</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">170 &#40;48&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">BMI&#44; kg&#47;m</span><span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;86 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Etiology</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">157 &#40;44&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ischemic heart disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80 &#40;22&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Others<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">114 &#40;32&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">NYHA functional class</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">I</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37 &#40;10&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">189 &#40;53&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">III</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">119 &#40;33&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;1&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Comorbidity</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Arterial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">255 &#40;72&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Atrial fibrillation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">205 &#40;58&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diabetes mellitus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">136 &#40;38&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>COPD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71 &#40;20&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sodium&#44; mEq&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">141&#46;7 &#40;4&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hemoglobin&#44; g&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;12 &#40;0&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>eGFR&#44; mL&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span> &#40;MDRD-4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;16 &#40;21&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cystatin&#44; mg&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;5 &#40;0&#46;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>NT-proBNP&#44; pg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6183 &#40;9575&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab1001134.png"
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Some patients can have several simultaneous etiologies&#46;</p>"
            ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of the clinical cohort&#46;</p>"
        ]
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; LV&#44; left ventricle&#59; LVEDD&#44; left ventricular end-diastolic diameter&#59; LVESD&#44; left ventricular end-systolic diameter&#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="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col"><span class="elsevierStyleItalic">n</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Media &#40;DE&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Correlation with CysC</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">R</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LV ejection fraction&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">348&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51&#46;75 &#40;13&#46;81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;071&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;197&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Left atrium diameter&#44; mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">272&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;77 &#40;9&#46;26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;082&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;179&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVEDD&#44; mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">268&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&#46;24 &#40;9&#46;62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;844&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVESD&#44; mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">263&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#46;47 &#40;11&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;033&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;599&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Septum thickness&#44; mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">271&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;53 &#40;2&#46;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;101&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;099&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posterior wall&#44; mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">268&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;43 &#40;2&#46;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;928&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Left ventricular mass&#44; g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">265&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">205&#46;61 &#40;82&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;903&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indexed LV mass&#44; g&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">265&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">118&#46;85 &#40;45&#46;35&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;856&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8220;Concentricity&#8221;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#42;&#42;</span></a>&#44; g&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">265&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;68 &#40;1&#46;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;081&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;197&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E-wave&#44; m&#47;s&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;99 &#40;0&#46;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;325&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">A-wave<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#42;&#42;</span></a>&#44; m&#47;s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;82 &#40;0&#46;33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;117&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;340&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E&#47;A ratio<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;25 &#40;0&#46;75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;907&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pulmonary artery systolic pressure&#44; mm Hg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">115&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46&#46;5 &#40;16&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;0&#46;063&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;509&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0015"
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; LA&#44; left atrium&#59; LVEDV&#44; left ventricular end-diastolic volume&#59; LVEF&#44; left ventricular ejection fraction&#59; LVESV&#44; left ventricular end-systolic volume&#59; sPAP&#44; systolic pulmonary artery pressure&#46;</p>"
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                  <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="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Full cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q1&#8804;1&#46;1<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q21&#46;11&#8211;1&#46;35<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q31&#46;36&#8211;1&#46;75<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Q4&#62;1&#46;75<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVEF&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51&#46;7 &#40;13&#46;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&#46;55 &#40;13&#46;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;65 &#40;14&#46;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49&#46;07 &#40;14&#46;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&#46;77 &#40;12&#46;82&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;075&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LA diameter&#44; mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;74 &#40;9&#46;27&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#46;36 &#40;9&#46;14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;95 &#40;8&#46;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;38 &#40;10&#46;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;31 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVEDV&#44; mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&#46;25 &#40;9&#46;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&#46;43 &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&#46;36 &#40;9&#46;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56&#46;56 &#40;9&#46;84&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;61 &#40;8&#46;39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;204&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LVESV&#44; mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#46;51 &#40;11&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#46;8 &#40;12&#46;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39 &#40;10&#46;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&#46;45 &#40;11&#46;76&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&#46;9 &#40;9&#46;66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Septum thickness&#44; mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;52 &#40;2&#46;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;18 &#40;2&#46;71&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;66 &#40;2&#46;02&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;56 &#40;2&#46;08&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;68 &#40;1&#46;99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;539&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Posterior wall thickness&#44; mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;42 &#40;2&#46;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;47 &#40;2&#46;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;38 &#40;1&#46;85&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2015.12.002

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