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Clinical and Molecular Study of 4 Cases of Pulmonary Hypertension Associated With Sarcoidosis
Estudio clínico y molecular de 4 casos de hipertensión pulmonar asociada a sarcoidosis
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=> true "cabecera" => "<span class="elsevierStyleTextfn">Case report</span>" "titulo" => "Clinical and Molecular Study of 4 Cases of Pulmonary Hypertension Associated With Sarcoidosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "e19" "paginaFinal" => "e21" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Adolfo Baloira Villar, Guillermo Pousada Fernández, Marta Núñez Fernández, Diana Valverde Pérez" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Adolfo" "apellidos" => "Baloira Villar" "email" => array:1 [ 0 => "adolfo.baloira.villar@sergas.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Guillermo" "apellidos" => "Pousada Fernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Marta" "apellidos" => "Núñez Fernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Diana" "apellidos" => "Valverde Pérez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Neumología, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Genética, Bioquímica e Inmunología, Facultad de Biología, Universidad de Vigo, Vigo, Pontevedra, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estudio clínico y molecular de 4 casos de hipertensión pulmonar asociada a sarcoidosis" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pulmonary hypertension (PH) can present as an isolated disease, in most cases without a defined cause, or can be associated with other diseases or exogenous agents, both toxins and drugs. Group 5 of the latest Nice clinical classification of the disease groups PH cases with unclear mechanisms, and encompasses very different diseases or conditions with very different pathogeneses, prognoses and treatment<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a>; sarcoidosis-associated PH, a very pleomorphic disease, is one of these. There is little information on the incidence, underlying changes, clinical presentation and therapeutic response of this type of PH, and in many cases what little there is has come from patients referred to lung transplant referral hospitals, or diagnosed solely by echocardiography.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">2,3</span></a> Like other chronic lung diseases that can progress to respiratory failure, PH (generally mild or moderate) is common in the advanced fibrotic stages of sarcoidosis, and it generally has little impact on prognosis.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a> In contrast, the PH observed in patients with lesser pulmonary involvement seems to be associated with significantly lower survival rates, and could perhaps benefit from specific treatment. This PH does not correlate with the severity of the underlying lung disease, and can appear even in the absence of radiological lung changes. Various mechanisms have been proposed to explain its development, such as destruction of the vascular bed and compression of the pulmonary vessels by lymphadenopathies or vasospasm.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">5</span></a> We report on a series of 4 patients diagnosed with sarcoidosis-associated PH using right heart catheterization, in whom pulmonary vasodilator drugs were administered.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical Findings</span><p id="par0010" class="elsevierStylePara elsevierViewall">Four patients (3 men and 1 woman) were seen in our PH Unit for sarcoidosis diagnosed by transbronchial biopsy and suspected PH between January 2004 and January 2013. Only 1 of the patients (case 4) had extrapulmonary involvement, which consisted of various nodular cutaneous lesions on both forearms; on biopsy, these were found to be histologically consistent with sarcoid granulomas. The clinical characteristics of the patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The diagnosis of sarcoidosis had preceded the onset of PH by a median of 5 years (4–6). The initial symptom was rapidly progressive dyspnea on exertion (time to diagnosis, 5–8 months). Three patients were classified in functional class (FC) III and one in FC IV. Bronchoalveolar lavage performed in 2 patients (2 and 3) showed lymphocytosis with predominantly CD4+ lymphocytes. Lung volumes were normal or near normal in all cases. Single-breath diffusing capacity (DLCO) ranged from 11% to 42% of theoretical values, with a significant decrease with respect to values prior to the onset of the PH (median 28% of the theoretical value). Chest computed tomography (CT) showed lymphadenopathies of less than 3<span class="elsevierStyleHsp" style=""></span>cm in all cases. Three patients had mild or moderate interstitial involvement consisting of peribronchovascular micronodules in cases 2 and 3, and fibrosis predominantly in the middle lung zones in case 4. No pulmonary artery thrombi were detected in any of the patients. All were receiving oral steroid treatment (10–20<span class="elsevierStyleHsp" style=""></span>mg/day of prednisone or equivalent). The systolic pulmonary artery pressure estimated by echocardiography ranged from 68 to 105<span class="elsevierStyleHsp" style=""></span>mmHg, with no significant left heart abnormalities in any of the patients. The distance walked in the 6<span class="elsevierStyleHsp" style=""></span>min walk test (6MWT) varied widely. The hemodynamic parameters obtained from diagnostic catheterization can be seen in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. In all cases, the patient had severe PH, with mean pulmonary artery pressure (mPAP) greater than 50<span class="elsevierStyleHsp" style=""></span>mmHg. Two patients had pre-capillary PH, while the other two were probably mixed disease (pre- and post-capillary).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Treatment with bosentan 125<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h was started in three cases (cases 1–3), and with tadalafil 40<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h in the other. A favorable response was initially observed (improvement of 1 FC and a mean of 80<span class="elsevierStyleHsp" style=""></span>m in the 6MWT) in 3 patients (cases 1, 3 and 4), although a new drug had to be added due to deterioration in cases 1 and 4 at months 5 and 7, respectively (case 1, sildenafil 40<span class="elsevierStyleHsp" style=""></span>mg/8<span class="elsevierStyleHsp" style=""></span>h, and case 4, ambrisentan 5<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h); an improvement was observed only in case 4. There was very little response in case 2, so sildenafil and later subcutaneous treprostinil were added. However, the patient continued to deteriorate, and was included on the lung transplant list (36 months after diagnosis). Two patients died: case 1 died 29 months after diagnosis due to vascular disease progression, and case 4 after 9 months (sudden death). Case 3 remains in FC II on monotherapy after 57 months of follow-up.</p><p id="par0020" class="elsevierStylePara elsevierViewall">After obtaining informed consent, a genetic study was carried out on the 4 patients. In case 1, a pathogenic mutation in gene <span class="elsevierStyleItalic">BMPR2</span> (Bone Morphogenetic Protein Receptor 2), c.1467G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>A (p.E489E) was found. Case 2 also had a potentially pathogenic mutation, c.622G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>T (p.E208*) in gene <span class="elsevierStyleItalic">KCNA5</span> (potassium voltage-gated channel, shaker-related subfamily, member 5), one of the voltage-dependent calcium channels that has been implicated in the pathogenesis of PH.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> Case 4 was a carrier of another pathogenic mutation in <span class="elsevierStyleItalic">BMPR2</span>, c. 484G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>C (p. A162P).</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">We present 4 patients with sarcoidosis-associated PH, including clinical data, therapeutic response and genetic study. This is the first study of this kind published in Spain. The prevalence of PH in this disease is not well known, and values ranging from 5% to 74% have been reported, the latter always in patients with very severe disease who have been referred for lung transplant assessment.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> A prospective single-center study with 111 patients diagnosed with sarcoidosis by means of a protocol that included right heart catheterization following a suspicious echocardiography found only 5 cases of PH, one of them post-capillary.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> Although the pathogenesis is not well understood, sarcoid granulomas on the pulmonary vessel walls are known to occur in over 60% of cases,<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> and some cases simulating pulmonary veno-occlusive disease have been reported in the literature.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> Due to cardiac and/or venous involvement, PH can have both a pre-capillary (30% of cases) and post-capillary component, as was the case in 2 of our patients. PH is diagnosed equally in both sexes, most often in the sixth decade of life. The initial symptom is usually dyspnea, with a mean survival of slightly less than 6 years.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> Given the paucity of published studies, it is unclear which variables could be associated with the development of PH. It is quite clear, however, that it can present with any degree of lung involvement. There are no studies on the correlation with extrapulmonary forms, either. Our 4 patients had little lung disease and near normal lung volumes at the time of PH diagnosis. A high grade of pulmonary fibrosis has been found to carry a poorer prognosis, although it is difficult to separate the impact of the PH from the fibrosis itself. None of our patients had any major fibrotic lesions, and death or transplant was undoubtedly affected by PH.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The possible involvement of steroid treatment in the evolution of sarcoidosis-associated PH is unclear, and data are contradictory. The few studies investigating various PH-specific drugs usually report hemodynamic improvement, especially in pulmonary vascular resistance and cardiac output, reduction in natriuretic peptides, increase of around 45–55<span class="elsevierStyleHsp" style=""></span>m in the distance walked in the 6MWT, with wide variability and differing results in FC classification. No comparative survival data are available. The outcome was satisfactory and long-term in only 1 of our 4 patients, with a modest response in another 2 cases and no response in the last. A 16-week, multicenter placebo-controlled randomized trial with bosentan was recently published, in which a significant improvement in hemodynamic parameters but no changes in the 6MWT were observed.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">One relevant finding in our series was the discovery of various potentially pathogenic mutations in 3 patients, particularly 2 cases with defects in <span class="elsevierStyleItalic">BMPR2</span>, the main gene associated with the onset of PH; one of the mutations changed the amino acid sequence of the protein and the other affected mRNA processing, producing a defective protein. The mutation detected in the <span class="elsevierStyleItalic">KCNA5</span> gene causes a stop codon that foreshortens the protein, which may interfere in its physiological role. As far as we know, no other genetic studies have been conducted in patients with sarcoidosis and PH. The presence of these mutations supports the multifactorial etiology of PH and sheds more light on the importance of genetics in the development of the disease.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, we present a small series of patients with PH and sarcoidosis treated with PH-specific drugs, with variable response. A genetic study showed some mutations in genes associated with this disease.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Funding</span><p id="par0045" class="elsevierStylePara elsevierViewall">This study has been partly funded by <span class="elsevierStyleGrantSponsor" id="gs1">Actelion</span>.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflict of Interests</span><p id="par0050" class="elsevierStylePara elsevierViewall">Adolfo Baloira has participated in remunerated meetings organized by Actelion, GSK, Pfizer and Lilly. The other authors declare that they have no conflict of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres468864" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec491514" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres468865" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec491513" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical Findings" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Funding" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of Interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-02-26" "fechaAceptado" => "2014-03-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec491514" "palabras" => array:3 [ 0 => "Pulmonary hypertension" 1 => "Sarcoidosis" 2 => "Mutations" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec491513" "palabras" => array:3 [ 0 => "Hipertensión pulmonar" 1 => "Sarcoidosis" 2 => "Mutaciones" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sarcoidosis is a pleomorphic disease that can present with pulmonary hypertension (PH). What little information is available about the association of these two diseases comes mainly from small series of patients scheduled for transplant. We present four cases of mild pulmonary involvement in whom right catheterisation was performed and PH-specific therapy was administered. After obtaining written consent, a genetic study was performed that showed mutations in PH-related genes in three of the patients. This is the first study of its kind to yield genetic information for this type of PH.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La sarcoidosis es una enfermedad pleomórfica que en ocasiones puede presentar hipertensión pulmonar (HP). Existe poca información sobre la asociación de estas 2 enfermedades, en muchos casos de pequeñas series de pacientes enviados para trasplante. Presentamos 4 casos con afectación pulmonar leve en los que se realizó cateterismo derecho y se utilizó tratamiento específico para HP. Tras consentimiento informado, se hizo un estudio genético que mostró mutaciones en genes relacionados con HP en 3 pacientes. Se trata del primer estudio que proporciona información genética en este tipo de HP.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Baloira Villar A, Pousada Fernández G, Núñez Fernández M, Valverde Pérez D. Estudio clínico y molecular de 4 casos de hipertensión pulmonar asociada a sarcoidosis. Arch Bronconeumol. 2015;51:e19–e21.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Age: at the time of PH diagnosis.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Years since onset: from diagnosis of sarcoidosis to diagnosis of PH.</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">FC: functional class; DLCO: CO diffusion as percentage of predicted value; FVC: forced vital capacity as percentage of predicted value; F: female; 6MWT: distance walked in 6<span class="elsevierStyleHsp" style=""></span>min at the time of diagnosis; M: male.</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"> \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">Case 1 \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">Case 2 \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">Case 3 \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">Case 4 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">59 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Years since onset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FVC (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">89 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">97 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">DLCO (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">6MWT (m) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">260 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">425 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">366 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">190 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab726056.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient Characteristics.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CI: cardiac index; mPAP: mean pulmonary artery pressure; sPAP: systolic pulmonary artery pressure; PCP: pulmonary capillary pressure; PVR: pulmonary vascular resistance.</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"> \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">Case 1 \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">Case 2 \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">Case 3 \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">Case 4 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">mPAP (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">sPAP (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">105 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">90 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PCP (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CI (l/min/m<span class="elsevierStyleSup">2</span>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.36 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">RVP (U Wood) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.96 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Vasodilator test \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Negative \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab726057.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Diagnostic Catheterization Results.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0065" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Updated clinical classification of pulmonary hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 3 | 8 |
| 2024 October | 40 | 19 | 59 |
| 2024 September | 48 | 20 | 68 |
| 2024 August | 72 | 33 | 105 |
| 2024 July | 53 | 20 | 73 |
| 2024 June | 68 | 28 | 96 |
| 2024 May | 72 | 36 | 108 |
| 2024 April | 31 | 24 | 55 |
| 2024 March | 75 | 13 | 88 |
| 2024 February | 47 | 26 | 73 |
| 2023 March | 8 | 5 | 13 |
| 2023 February | 37 | 19 | 56 |
| 2023 January | 24 | 36 | 60 |
| 2022 December | 51 | 33 | 84 |
| 2022 November | 45 | 33 | 78 |
| 2022 October | 46 | 28 | 74 |
| 2022 September | 28 | 36 | 64 |
| 2022 August | 35 | 39 | 74 |
| 2022 July | 31 | 56 | 87 |
| 2022 June | 29 | 44 | 73 |
| 2022 May | 40 | 35 | 75 |
| 2022 April | 28 | 32 | 60 |
| 2022 March | 27 | 47 | 74 |
| 2022 February | 36 | 31 | 67 |
| 2022 January | 19 | 35 | 54 |
| 2021 December | 35 | 36 | 71 |
| 2021 November | 27 | 39 | 66 |
| 2021 October | 47 | 40 | 87 |
| 2021 September | 24 | 35 | 59 |
| 2021 August | 20 | 42 | 62 |
| 2021 July | 26 | 28 | 54 |
| 2021 June | 28 | 36 | 64 |
| 2021 May | 41 | 43 | 84 |
| 2021 April | 94 | 94 | 188 |
| 2021 March | 77 | 52 | 129 |
| 2021 February | 52 | 23 | 75 |
| 2021 January | 36 | 31 | 67 |
| 2020 December | 24 | 29 | 53 |
| 2020 November | 18 | 16 | 34 |
| 2020 October | 18 | 16 | 34 |
| 2020 September | 31 | 19 | 50 |
| 2020 August | 18 | 22 | 40 |
| 2020 July | 24 | 24 | 48 |
| 2020 June | 18 | 12 | 30 |
| 2020 May | 30 | 8 | 38 |
| 2020 April | 35 | 18 | 53 |
| 2020 March | 27 | 17 | 44 |
| 2020 February | 34 | 12 | 46 |
| 2020 January | 26 | 15 | 41 |
| 2019 December | 22 | 11 | 33 |
| 2019 November | 21 | 21 | 42 |
| 2019 October | 25 | 13 | 38 |
| 2019 September | 47 | 11 | 58 |
| 2019 August | 35 | 17 | 52 |
| 2019 July | 25 | 20 | 45 |
| 2019 June | 21 | 19 | 40 |
| 2019 May | 28 | 16 | 44 |
| 2019 April | 18 | 30 | 48 |
| 2019 March | 34 | 19 | 53 |
| 2019 February | 39 | 25 | 64 |
| 2019 January | 47 | 27 | 74 |
| 2018 December | 38 | 15 | 53 |
| 2018 November | 86 | 27 | 113 |
| 2018 October | 120 | 22 | 142 |
| 2018 September | 40 | 10 | 50 |
| 2018 May | 42 | 0 | 42 |
| 2018 April | 68 | 7 | 75 |
| 2018 March | 76 | 12 | 88 |
| 2018 February | 69 | 9 | 78 |
| 2018 January | 162 | 6 | 168 |
| 2017 December | 91 | 12 | 103 |
| 2017 November | 18 | 4 | 22 |
| 2017 October | 26 | 7 | 33 |
| 2017 September | 19 | 10 | 29 |
| 2017 August | 22 | 12 | 34 |
| 2017 July | 18 | 8 | 26 |
| 2017 June | 34 | 21 | 55 |
| 2017 May | 34 | 8 | 42 |
| 2017 April | 41 | 13 | 54 |
| 2017 March | 18 | 11 | 29 |
| 2017 February | 15 | 9 | 24 |
| 2017 January | 10 | 4 | 14 |
| 2016 December | 22 | 8 | 30 |
| 2016 November | 42 | 12 | 54 |
| 2016 October | 43 | 22 | 65 |
| 2016 September | 39 | 14 | 53 |
| 2016 August | 44 | 12 | 56 |
| 2016 July | 47 | 17 | 64 |
| 2016 May | 1 | 0 | 1 |
| 2016 March | 2 | 0 | 2 |
| 2015 December | 3 | 0 | 3 |
| 2015 October | 32 | 3 | 35 |
| 2015 September | 33 | 12 | 45 |
| 2015 August | 48 | 9 | 57 |
| 2015 July | 36 | 14 | 50 |
| 2015 May | 0 | 1 | 1 |
| 2015 April | 2 | 1 | 3 |
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