Long-term effect of bosentan in pulmonary hypertension associated with complex congenital heart disease | Revista Portuguesa de Cardiologia (English edition)

array:24 ["pii" => "S2174204913000433" "issn" => "21742049" "doi" => "10.1016/j.repce.2013.02.005" "estado" => "S300" "fechaPublicacion" => "2013-02-01" "aid" => "194" "copyright" => "Sociedade Portuguesa de Cardiologia" "copyrightAnyo" => "2012" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Cardiol. 2013;32:123-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3395 "formatos" => array:3 [ "EPUB" => 153 "HTML" => 2593 "PDF" => 649 ] ] "itemSiguiente" => array:19 [ "pii" => "S2174204913000445" "issn" => "21742049" "doi" => "10.1016/j.repce.2013.02.006" "estado" => "S300" "fechaPublicacion" => "2013-02-01" "aid" => "206" "copyright" => "Sociedade Portuguesa de Cardiologia" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Cardiol. 2013;32:131-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 4259 "formatos" => array:3 [ "EPUB" => 155 "HTML" => 3420 "PDF" => 684 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Mitral valve replacement combined with coronary artery bypass graft surgery in patients with moderate-to-severe ischemic mitral regurgitation" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "131" "paginaFinal" => "137" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Substituição da valva mitral combinada com cirurgia de revascularização do miocárdio em pacientes com regurgitação mitral isquémica moderada a grave" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1236 "Ancho" => 1597 "Tamanyo" => 61087 ] ] "descripcion" => array:1 [ "en" => "Improvement in left ventricular ejection fraction by echocardiography after surgery. Values expressed as mean±standard deviation. CABG: coronary artery bypass grafting; MVR: mitral valve replacement; Postop: postoperative." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Michel Pompeu B.O. Sá, Evelyn F. Soares, Cecília A. Santos, Omar J. Figueiredo, Renato O.A. Lima, Rodrigo R. Escobar, Frederico P. Vasconcelos, Ricardo C. Lima" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Michel Pompeu B.O." "apellidos" => "Sá" ] 1 => array:2 [ "nombre" => "Evelyn F." "apellidos" => "Soares" ] 2 => array:2 [ "nombre" => "Cecília A." "apellidos" => "Santos" ] 3 => array:2 [ "nombre" => "Omar J." "apellidos" => "Figueiredo" ] 4 => array:2 [ "nombre" => "Renato O.A." "apellidos" => "Lima" ] 5 => array:2 [ "nombre" => "Rodrigo R." "apellidos" => "Escobar" ] 6 => array:2 [ "nombre" => "Frederico P." "apellidos" => "Vasconcelos" ] 7 => array:2 [ "nombre" => "Ricardo C." "apellidos" => "Lima" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204913000445?idApp=UINPBA00004E" "url" => "/21742049/0000003200000002/v1_201305171228/S2174204913000445/v1_201305171228/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2174204913000421" "issn" => "21742049" "doi" => "10.1016/j.repce.2013.02.004" "estado" => "S300" "fechaPublicacion" => "2013-02-01" "aid" => "210" "copyright" => "Sociedade Portuguesa de Cardiologia" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Cardiol. 2013;32:117-22" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3869 "formatos" => array:3 [ "EPUB" => 156 "HTML" => 3094 "PDF" => 619 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "High-sensitivity C-reactive protein predicts adverse outcomes after non-ST-segment elevation acute coronary syndrome regardless of GRACE risk score, but not after ST-segment elevation myocardial infarction" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "117" "paginaFinal" => "122" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "O valor do teste de alta sensibilidade da proteína C-reativa como preditor de resultados adversos em doentes com síndrome coronária aguda" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1535 "Ancho" => 1562 "Tamanyo" => 67469 ] ] "descripcion" => array:1 [ "en" => "Receiver operating characteristic curve for high-sensitivity C-reactive protein in predicting follow-up outcomes (cardiac death and re-infarction). Area under the curve: 0.75±0.05." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sergio Raposeiras Roubín, Cristina Barreiro Pardal, Filomena Roubín-Camiña, Raymundo Ocaranza Sanchez, Ezequiel Álvarez Castro, Beatriz Paradela Dobarro, Jose María García-Acuña, Pablo Aguiar Souto, Michel Jacquet Hervet, Maria José Castromán, Isabel Arufe, Belén Outes, María Victoria Reino-Maceiras, Emad Abu Assi, José Ramón González-Juanatey" "autores" => array:15 [ 0 => array:2 [ "nombre" => "Sergio" "apellidos" => "Raposeiras Roubín" ] 1 => array:2 [ "nombre" => "Cristina" "apellidos" => "Barreiro Pardal" ] 2 => array:2 [ "nombre" => "Filomena" "apellidos" => "Roubín-Camiña" ] 3 => array:2 [ "nombre" => "Raymundo" "apellidos" => "Ocaranza Sanchez" ] 4 => array:2 [ "nombre" => "Ezequiel" "apellidos" => "Álvarez Castro" ] 5 => array:2 [ "nombre" => "Beatriz" "apellidos" => "Paradela Dobarro" ] 6 => array:2 [ "nombre" => "Jose María" "apellidos" => "García-Acuña" ] 7 => array:2 [ "nombre" => "Pablo" "apellidos" => "Aguiar Souto" ] 8 => array:2 [ "nombre" => "Michel" "apellidos" => "Jacquet Hervet" ] 9 => array:2 [ "nombre" => "Maria José" "apellidos" => "Castromán" ] 10 => array:2 [ "nombre" => "Isabel" "apellidos" => "Arufe" ] 11 => array:2 [ "nombre" => "Belén" "apellidos" => "Outes" ] 12 => array:2 [ "nombre" => "María Victoria" "apellidos" => "Reino-Maceiras" ] 13 => array:2 [ "nombre" => "Emad" "apellidos" => "Abu Assi" ] 14 => array:2 [ "nombre" => "José Ramón" "apellidos" => "González-Juanatey" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204913000421?idApp=UINPBA00004E" "url" => "/21742049/0000003200000002/v1_201305171228/S2174204913000421/v1_201305171228/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Long-term effect of bosentan in pulmonary hypertension associated with complex congenital heart disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "123" "paginaFinal" => "129" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Rui Baptista, Graça Castro, António Marinho da Silva, Pedro Monteiro, Luís Augusto Providência" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Rui" "apellidos" => "Baptista" "email" => array:1 [ 0 => "ruibaptista@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0005" ] 2 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Graça" "apellidos" => "Castro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 2 => array:3 [ "nombre" => "António Marinho" "apellidos" => "da Silva" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 3 => array:3 [ "nombre" => "Pedro" "apellidos" => "Monteiro" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Luís Augusto" "apellidos" => "Providência" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidade de Hipertensão Pulmonar, Serviço de Cardiologia, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal" "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal" "etiqueta" => "b" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Efeito a longo-prazo do bosentano na hipertensão pulmonar associada a cardiopatias congénitas complexas" ] ] "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" => 896 "Ancho" => 1472 "Tamanyo" => 68568 ] ] "descripcion" => array:1 [ "en" => "Effect of six months of bosentan therapy on WHO functional class." ] ] ] "textoCompleto" => "IntroductionEisenmenger syndrome (ES) is defined as significant pulmonary arterial hypertension (PAH) in conjunction with congenital heart disease (CHD) and shunt reversal,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> and comprises about 1% of all CHD.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Although caused by a defect in the heart, ES is a multiorgan disorder associated with numerous life-threatening complications, including hemoptysis, cerebrovascular accidents, brain abscesses, arrhythmias and syncope.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> The majority of patients who develop ES survive to adulthood, but markedly diminished exercise tolerance with reduced life expectancy is the rule.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Although their survival is better than in idiopathic pulmonary arterial hypertension (IPAH), ES patients share many histopathological similarities with IPAH.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>These similarities made the use of pulmonary vasodilators in this subset of patients an attractive option. In the BREATHE-5 study, the first placebo-controlled trial in patients with ES, the endothelin-receptor antagonist (ETRA) bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation,<a class="elsevierStyleCrossRef" href="#bib0030">6</a> and these results were further supported by the open-label extension of this pivotal trial.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> However, BREATHE-5 only included ES patients with simple CHD (atrial septal defect, ventricular septal defect or both), excluding patients with complex CHD, patent ductus arteriosus or segmental pulmonary hypertension as in pulmonary atresia. Evidence for the use of bosentan in this patient subset is only available in the form of series with small samples or short follow-up.<a class="elsevierStyleCrossRefs" href="#bib0040">8–10</a> Moreover, due to the progressive nature of the disease,<a class="elsevierStyleCrossRef" href="#bib0030">6</a> some patients may still have a negative evolution even though treated with advanced therapies, highlighting the need for combination therapy. In the only randomized controlled trial on combination therapy in ES, the addition of sildenafil to ongoing bosentan failed to improve walking distance or pulmonary vascular resistance.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>The aims of our study were (i) to assess the safety of bosentan and its short-term effects on systemic oxygen saturation and exercise capacity in patients with complex CHD and PAH, and (ii) to perform a long-term follow-up to assess efficacy and safety of bosentan treatment and the need for combination therapy in this group of complex CHD patients.MethodsParticipantsWe prospectively collected data on a dedicated database of all patients with PAH due to complex CHD, who were being followed or were referred to our tertiary center between August 2003 and July 2009. All patients had complex CHD, with Eisenmenger physiology (non-restrictive intra- or extracardiac communication with a right-to-left shunt at rest and high pulmonary vascular resistance) or with severe PAH. Right heart catheterization was performed in all patients to confirm the diagnosis before treatment initiation. Patients with isolated atrial or ventricular septal defects were excluded from the analysis. Functional class was II–IV in all participants, assessed by the World Health Organization (WHO) classification. All pulmonary vasodilator prescriptions were authorized by the pharmacy and this investigation conformed to the principles outlined in the Declaration of Helsinki. The local ethics committee approved the research protocol and informed consent was obtained from all subjects. Data up to May 2011 were analyzed.MedicationBosentan treatment was initiated at a dose of 62.5 mg bid. After one month, if no adverse effects occurred, the dosage was doubled to 125 mg bid and maintained thereafter. Baseline and monthly hemoglobin and liver function tests were obtained. Treatment with prostanoids, phosphodiesterase V inhibitors and other endothelin receptor antagonists was not allowed before the introduction of bosentan. Based on patients’ overall clinical assessment, the team of attending physicians (including a cardiologist with specialization in adult congenital heart disease [GC] and a pediatric cardiologist [AMS]) was authorized to add sildenafil to the ongoing therapy in a starting dosage of 20 mg tid up to 50 mg tid. All patients had a baseline iron status assessment and bosentan therapy was initiated only after correction of anemia and/or iron deficiency.Follow-up and final assessmentClinical follow-up was performed by a monthly clinical visit to our hospital in the first six months of treatment and in three-month periods thereafter.Six-minute walking testSubmaximal exercise capacity was assessed by the six-minute walking test (6MWT). This test was conducted by three experienced operators in a 30-m indoor marked corridor, according to the guidelines of the American Thoracic Society.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Heart rate, pulse oximetry and Borg dyspnea score were recorded at baseline and six minutes in all tests.Statistical analysisContinuous variables are expressed as means ± standard deviation and categorical variables by percentages. Pairwise comparison between baseline and follow-up continuous variables was performed using the paired Student's t test. Due to the small sample size, all variables were tested for normality using the Kolmogorov-Smirnov test. Categorical variables at baseline and follow-up were compared using Fisher's test. All p-values were two-sided and a p-value less than 0.05 was considered to indicate statistical significance. Analyses and calculations were performed using SPSS version 13.0 (Chicago, USA).ResultsBaseline demographics and characteristicsPatients’ baseline characteristics are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Fourteen patients were enrolled in the treatment protocol. Mean age was 37.1±11.7 years and half of the patients were female. The most common diagnosis was pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (35.7%) (one patient had a palliative Blalock-Taussig shunt), followed by truncus arteriosus with ventricular septal defect (28.6%), patent ductus arteriosus with ventricular septal defect (21.4%) and transposition of the great arteries (14.3%) (one patient underwent a Mustard procedure). More than half of the patients were taking diuretics (57.1%) and six had an oxygen prescription; no patient was taking warfarin. At baseline, all patients were normotensive (mean 114±17/71±24 mmHg), with heart rates in the high normal range (mean 88±12 bpm). Baseline hemoglobin was elevated (17.9±2.1 g/dl); all patients had normal liver function tests. Hemodynamic findings were remarkable for a very high mean pulmonary artery systolic pressure (79.6±31.3 mmHg). Regarding functional capacity, more than 90% of patients were in WHO class III or IV. Only one patient was in WHO class II before starting bosentan. No phlebotomies were conducted in the cohort.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Exposure to bosentan and need for combination therapyMedian exposure to bosentan was 43 (interquartile range 30-67) months. One patient discontinued bosentan after 16 months of usage due to low treatment adherence secondary to lower limb edema and was started on sildenafil. During long-term follow-up, four patients were started on sildenafil and one on triple combination therapy with intravenous iloprost due to progressive heart failure. Sildenafil was added after a median bosentan treatment duration of 38 months. Patients who needed combination therapy had a lower six-month 6MWT response after bosentan initiation (+22 m) compared to patients who did not need therapeutic escalation during long-term follow-up (+85 m). <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> summarizes the data for each patient.Exercise capacity and World Health Organization functional classAfter six months of bosentan treatment, 6MWD increased in 12 and decreased two patients. The mean increase in 6MWD was 56.5 m, from 371.9±90.3 to 428.4±98.3 m (p=0.005) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Changes in functional class were significant, as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>. After a median follow-up of four years, mean 6MWD for patients on bosentan monotherapy (n=8) was 440.1±103.8 m, whereas for patients on bosentan-sildenafil combination therapy (n=4) it was 428.8±96.9 m (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Regarding functional class, after a mean six months of treatment with bosentan, nine patients were in class I or II and five patients remained in class III (p=0.005). No patient experienced worsening in functional class.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Results in patients with segmental pulmonary hypertension due to pulmonary atresia (n=5) were similar to those of the overall population. After six months, mean 6MWD improved from 352.6±93.2 m to 454.0±72.7 m (p=0.043). The improvement in functional capacity was maintained at four years (451.8±54.7 m, p=0.043 vs. baseline and p=0.933 vs. six months). No differences were found regarding oxygen saturation pre- and post-exercise; no patient required therapeutic escalation.Safety, morbidity and mortalityOne patient required discontinuation of bosentan due to lower limb edema. No significant rise in liver transaminases was seen during follow-up and none of the patients had levels exceeding three times the upper limit of the reference range. No signs of decreased oxygen saturation were seen.Two patients (14.3%), both with truncus arteriosus, died during follow-up after 48 months of vasodilator therapy. One patient (age 45) on bosentan monotherapy died due to a complicated cerebral abscess. The second patient (age 48), on triple combination therapy, died of decompensated heart failure. Survival rates in patients with complex CHD at one, two and four years were 100%, 100% and 85.7%, respectively.DiscussionIn patients with PAH and complex CHD, bosentan was a safe, well tolerated and effective therapy. The effects on 6MWT were evident after six months and were sustained in long-term follow-up. The safety and drug tolerance were similar to those reported in the IPAH and BREATHE-5 studies, with no serious side effects occurring during this long follow-up period.Patients with PAH and complex CHD have a better long-term prognosis than those with IPAH,<a class="elsevierStyleCrossRef" href="#bib0065">13</a> mainly due to preservation of biventricular function until the later stages of disease. Some authors suggest that the right ventricle is ‘primed’ for a lifetime of functioning at systemic level pressure, with persistence of a protective fetal morphology.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Unfortunately, and in contrast to previous claims that the hemodynamics of patients with ES was stable over time, the BREATHE-5 study demonstrated that even in a limited 16-week follow-up, indicators of progressive vascular disease, such as pulmonary vascular resistance index, worsened in the placebo group.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>The available evidence regarding the use of disease-targeting therapies has recently been reviewed elsewhere.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> The pivotal role of endothelin-1 in the development of pulmonary vasculopathy made the use of ETRA attractive and several studies, including one randomized controlled trial, established the benefit of ETRA in ES patients with simple defects.<a class="elsevierStyleCrossRefs" href="#bib0015">3,5</a> The evidence for sildenafil or prostacyclins is based on smaller studies.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> However, BREATHE-5 excluded patients with complex CHD and a recent single-center, randomized placebo-controlled study with 21 patients had only one patient with complex disease. Although it was thought that the location of the shunt (pre-tricuspid versus post-tricuspid) would influence treatment outcomes,<a class="elsevierStyleCrossRef" href="#bib0085">16</a> a subgroup analysis of the BREATHE-5 study and two recent reports do not support this hypothesis.<a class="elsevierStyleCrossRefs" href="#bib0045">9,17</a> Moreover, a comparison of patients with persistent PAH after shunt closure and ES patients found no differences in four-year survival.<a class="elsevierStyleCrossRef" href="#bib17">17</a>After the use of bosentan, we noted a significant improvement in exercise capacity and in WHO functional class, with no decrease in Borg dyspnea score, indicating that these patients increased their exercise capacity with a similar level of perceived dyspnea. Moreover, mean six-month improvement in 6MWD was 56 m, similar to other reports, including patients with non-complex disease<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and with IPAH.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Our results reproduce, in a larger population, the findings of Diaz-Caraballo et al., the only study to date focusing solely on complex congenital heart disease. In that study, mean 6MWD improved significantly at six months (from 266±161 to 343±121 m, p=0.045), the change being maintained at two years.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> We extend these findings to a four-year follow-up.We also included pulmonary atresia patients, a distinct subgroup, as they present with segmental pulmonary hypertension and no shunt reversal. Little evidence is available regarding the role of pulmonary vasodilators in these patients. A recent report by Schuuring et al. on seven patients demonstrates a 62-m improvement in 6MWD after one year of bosentan treatment.<a class="elsevierStyleCrossRef" href="#bib10">10</a> Our results are similar, with a significant improvement in walking distance at six months, sustained in the long term. Interestingly, none of the patients needed combination therapy. The mechanism whereby bosentan acts on this subset of patients is not known, but may be related to its action on the endothelin pathway.Although not evidence-based but in line with recommendations for IPAH,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> combination therapy with sildenafil was initiated in four patients due to disease progression, reflecting the high-risk group that was studied and the progressive nature of the disease during long-term follow-up. It is noteworthy that the four patients who underwent therapeutic escalation remained clinically stable for almost four years before the initiation of sildenafil.Patients with PAH and complex CHD are at high risk of death<a class="elsevierStyleCrossRef" href="#bib0095">18</a> but there is a paucity of data regarding survival in such patients under vasodilator therapy. In our cohort, total mortality was 14% at four years, which is higher than in the series by Dimopoulos et al.<a class="elsevierStyleCrossRef" href="#bib0100">19</a> (around 3% at two years), lower than that reported by Vis et al.<a class="elsevierStyleCrossRef" href="#bib17">17</a> (20% at four years), but similar to the recently published results by Monfredi et al.<a class="elsevierStyleCrossRef" href="#bib20">20</a> Differences in study design, follow-up duration and population selection may be responsible for these disparities.The safety of bosentan in this high-risk population was remarkable. No patient experienced a rise in liver enzymes exceeding three times the upper limit of normal or systemic hypotension. Only one patient discontinued bosentan due to lower limb edema. Moreover, and in line with previous reports, no changes were noted in systemic oxygenation. This may be due to the limited influence of bosentan on the net right-to-left shunt because its effects on both pulmonary and systemic vascular resistance are similar.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>This was a non-randomized, single-center study, with a limited number of patients reflecting the rarity of this condition. It represents a cohort of patients being followed in a specialized pulmonary hypertension clinic. Our small sample precludes further comparisons between different types of congenital defects. Although only patients with right heart catheterization-confirmed pulmonary hypertension were included in this study, the heterogeneity of the congenital lesions causing it may have influenced clinical evolution, themselves affecting the outcome. An example is truncal valve regurgitation in truncus arteriosus patients; both patients who died had severe regurgitation that may have contributed to their dismal prognosis. Several factors can influence exercise capacity in ES patients, including iron status,<a class="elsevierStyleCrossRef" href="#bib0110">21</a> associated cardiac lesions or pulmonary comorbidities; however, our results regarding exercise capacity and functional status were consistent with other studies in patients without complex congenital disease, suggesting that bosentan has a true therapeutic effect; all patients had regular iron status assessments and correction as needed. We did not perform hemodynamic re-evaluation of patients after pulmonary vasodilator therapy; all clinical decisions regarding therapeutic escalation were made in the light of clinical, laboratorial, echocardiographic and functional data.ConclusionsBosentan was safe and was associated with improved exercise capacity in patients with complex congenital heart disease and PAH. The improvement in exercise capacity was maintained up to four years and the longer-term safety profile was similar to that reported in simple congenital heart disease patients.Conflicts of interestGraça Castro and António Marinho da Silva are consultants for Actelion Portugal. Rui Baptista has received funding for research from Actelion Portugal. Pedro Monteiro and Luís Augusto Providência have no relationships relevant to the contents of this paper to disclose." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres177659" "titulo" => array:6 [ 0 => "Abstract" 1 => "Background" 2 => "Objectives" 3 => "Methods" 4 => "Results" 5 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec166312" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres177658" "titulo" => array:6 [ 0 => "Resumo" 1 => "Introdução" 2 => "Objectivos" 3 => "Métodos" 4 => "Resultados" 5 => "Conclusões" ] ] 3 => array:2 [ "identificador" => "xpalclavsec166313" "titulo" => "Palavras chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Participants" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Medication" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Follow-up and final assessment" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Six-minute walking test" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Baseline demographics and characteristics" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Exposure to bosentan and need for combination therapy" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Exercise capacity and World Health Organization functional class" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Safety, morbidity and mortality" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack45567" "titulo" => "Acknowledgement" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-01-17" "fechaAceptado" => "2012-02-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec166312" "palabras" => array:3 [ 0 => "Bosentan" 1 => "Congenital heart disease" 2 => "Pulmonary hypertension" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras chave" "identificador" => "xpalclavsec166313" "palabras" => array:3 [ 0 => "Bosentan" 1 => "Cardiopatia congénita" 2 => "Hipertensão pulmonar" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "BackgroundBosentan is recommended for symptomatic patients with Eisenmenger syndrome due to simple congenital lesions such as atrial and ventricular septal defects (VSD). However, its long-term efficacy and safety in patients with pulmonary arterial hypertension (PAH) associated with complex congenital heart disease (CHD) is unknown. ObjectivesWe examined the short- and long-term effects and safety profile of bosentan in patients with PAH and complex CHD. MethodsWe followed 14 patients with PAH and complex CHD for a mean of four years. Demographic parameters, exercise capacity assessed by the six-minute walking test (6MWT) and oxygen saturation were assessed at baseline, six months and at follow-up. ResultsMean age was 37.1±11.7 years; 90% were in WHO class III or IV. The most common diagnosis was pulmonary atresia with VSD (35.7%), followed by truncus arteriosus (28.6%), patent ductus arteriosus (21.4%) and transposition of the great arteries (14.3%). After six months of treatment, six-minute walking distance (6MWD) increased from 371.9 to 428.4 m (p=0.005) and functional class was improved (p=0.005). After four years, one patient discontinued bosentan due to side effects and four patients were started on sildenafil, after a mean 38 months of bosentan treatment. Mean 6MWD for patients on bosentan monotherapy (n=8) was 440.1±103.8 m, whereas for patients on bosentan-sildenafil combination therapy (n=4) it was 428.8±96.9 m, after four years of therapy. Two patients died during follow-up. ConclusionsBosentan was safe and was associated with improved exercise capacity in patients with PAH and complex CHD. This improvement was sustained for up to four years and the safety profile was similar to simple CHD patients." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "IntroduçãoO bosentano é recomendado em doentes com hipertensão arterial pulmonar (HAP) associada a lesões congénitas simples, como comunicações interventriculares (CIV). Contudo, a sua eficácia e segurança a longo prazo em doentes com HAP associada a cardiopatias congénitas complexas (HAP-CCC) é desconhecida. ObjectivosAvaliámos a eficácia e segurança a curto e longo-prazo do bosentano na HAP-CCC. MétodosEstudaram-se 14 doentes com HAP-CCC, relativamente a parâmetros demográficos, capacidade funcional avaliada pelo teste de marcha de seis minutos (TM6M) e saturação de oxigénio, antes de iniciar terapêutica, aos seis meses e durante o período de seguimento clínico a longo-prazo (quatro anos). ResultadosNoventa por cento dos doentes encontravam-se em classe OMS III ou IV, com idade média de 37,1 ± 11,7 anos. O diagnóstico mais frequente foi a atrésia pulmonar com CIV (35,7%), seguida de truncus arteriosus (28,6%), canal arterial patente (21,4%) e transposição de grandes vasos (14,3%). Após seis meses de tratamento, o TM6M aumentou de 371,9 para 428,4 metros (p = 0,005) e a classe funcional melhorou (p = 0,005). Após quatro anos, um doente suspendeu bosentano devido a efeitos secundários e quatro doentes iniciaram sildenafil, após uma duração média de monoterapia de 38 meses. Após quatro anos de terapêutica, nos doentes em monoterapia com bosentano (n = 8) o TM6M foi de 440,1 ± 103,8 metros, enquanto que nos doentes com bosentano-sildenafil (n = 4) foi de 428,8 ± 96,9 metros. Dois doentes faleceram durante o período de seguimento clínico. ConclusõesO bosentano foi seguro e esteve associado a melhoria na capacidade funcional em doentes com HAP-CCC até aos quatro anos de seguimento clínico." ] ] "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" => 896 "Ancho" => 1472 "Tamanyo" => 68568 ] ] "descripcion" => array:1 [ "en" => "Effect of six months of bosentan therapy on WHO functional class." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Clinical characteristics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">n=14 \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age, years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37.1±11.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Female gender, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (50) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diagnosis</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Truncus arteriosus, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (28.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Transposition of the great arteries, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (14.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pulmonary atresia with ventricular septal defect, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (35.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patent ductus arteriosus, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (21.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Medications</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Warfarin, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Digoxin, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (21.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diuretics, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (57.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean daily furosemide dosage (mg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Beta-blockers, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (7.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oxygen, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (42.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Laboratory variables</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemoglobin, g/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17.9±2.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean corpuscular volume, fl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89.0±5.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Creatinine, mg g/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.8±0.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alanine aminotransferase, U/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18.4±4.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemodynamic variables</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean pulmonary artery pressure, mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79.6±31.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab272096.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "O2 Sat: oxygen saturation; SBP: systolic blood pressure. WHO: World Health Organization functional class." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Baselinen=14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">6 monthsn=14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mean difference (95% CI) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heart rate, beats/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">88±12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90±14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (−5-9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.765 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Systolic blood pressure, mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">114±17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">119±12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (−3-13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.170 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diastolic blood pressure, mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71±24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59±12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−12 (−28-4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.125 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WHO class</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (7.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (7.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (57.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (78.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (35.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (14.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.895 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Six-minute walking distance, m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">371.9±90.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">428.4±98.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56.5 (14.3-98.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.005 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Systemic O2Sat at rest, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82.0±6.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81.9±6.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.1 (−2.7-2.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.956 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Systemic O2Sat at peak exercise, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.4±13.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72.8±10.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.6 (−5.1-6.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.832 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peak SBP, mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123±16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">130±13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.0 (−0.3-14.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.058 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Borg dyspnea score, baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4±1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.3±2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.9 (−0.8-2.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.271 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Borg dyspnea score after exercise \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.7±1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.5±1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.8 (−0.2-1.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.108 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab272095.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical characteristics at baseline and six months after bosentan therapy." ] ] 3 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "6MWD: six-minute walking distance, in m." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Follow-up timePatients on bosentan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baselinen=14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Six monthsn=14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Three yearsn=13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Four yearsn=8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p(trend) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6MWD, m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">371.9±90.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">428.4±98.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">439.5±97.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">440.1±103.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.005 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab272094.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Long-term effect of bosentan monotherapy on exercise capacity." ] ] 4 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "DOB: date of birth; F: female; M: male; PDA: patent ductus arteriosus; RHF: right heart failure; 6M: six-month; 6MWD: six-minute walking distance, in m; TA: truncus arteriosus; TGA: transposition of the great arteries; VSD: ventricular septal defect; WHO: World Health Organization functional class." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">DOB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Gender \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Vital status \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">WHO initial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">6MWT initial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Bosentan start date \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">WHO6M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">6MWT6M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Sildenafil start date \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">6MWT prior \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">6MWD6M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">WHO6M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Date of death \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Cause of death \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 Jan 63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDA and VSD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">258 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Jun 04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">218 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aug 08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">370 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">392 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 Jun 70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">517 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Jan 07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">550 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Feb 10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">450 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">540 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 Aug 93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDA and VSD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">441 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aug 03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">490 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Feb 10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">410 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">468 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 Jul 61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Deceased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">324 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aug 05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">370 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apr 08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">180 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aug 09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RHF \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab272093.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Individual data for patients that required therapeutic escalation." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:21 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. Wood" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br Med J" "fecha" => "1958" "volumen" => "2" "paginaInicial" => "755" "paginaFinal" => "762" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/519181" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "M.G. Duffels" 1 => "P.M. Engelfriet" 2 => "R.M. Berger" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2006.09.017" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2007" "volumen" => "120" "paginaInicial" => "198" "paginaFinal" => "204" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17182132" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ESC guidelines for the management of grown-up congenital heart disease (new version 2010)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "H. Baumgartner" 1 => "P. Bonhoeffer" 2 => "N.M. De Groot" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehq249" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2010" "volumen" => "31" "paginaInicial" => "2915" "paginaFinal" => "2957" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20801927" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Poor prognosis and related factors in adults with Eisenmenger syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "H. Oya" 1 => "N. Nagaya" 2 => "M. Uematsu" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am Heart J" "fecha" => "2002" "volumen" => "143" "paginaInicial" => "739" "paginaFinal" => "744" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11923814" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "N. Galie" 1 => "M.M. Hoeper" 2 => "M. Humbert" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehp297" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2009" "volumen" => "30" "paginaInicial" => "2493" "paginaFinal" => "2537" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19713419" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "N. Galie" 1 => "M. Beghetti" 2 => "M.A. Gatzoulis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.106.630715" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2006" "volumen" => "114" "paginaInicial" => "48" "paginaFinal" => "54" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16801459" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "M.A. Gatzoulis" 1 => "M. Beghetti" 2 => "N. Galie" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2007.04.078" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2008" "volumen" => "127" "paginaInicial" => "27" "paginaFinal" => "32" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17658633" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term bosentan treatment of complex congenital heart disease and Eisenmenger's syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "E. Diaz-Caraballo" 1 => "A.E. Gonzalez-Garcia" 2 => "M. Renones" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Esp Cardiol" "fecha" => "2009" "volumen" => "62" "paginaInicial" => "1046" "paginaFinal" => "1049" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19712626" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The efficacy and safety of sildenafil in patients with pulmonary arterial hypertension associated with the different types of congenital heart disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "W.-J. Zeng" 1 => "X.-L. Lu" 2 => "C.-M. Xiong" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/clc.20917" "Revista" => array:6 [ "tituloSerie" => "Clin Cardiol" "fecha" => "2011" "volumen" => "34" "paginaInicial" => "513" "paginaFinal" => "518" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21678455" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of segmental pulmonary artery hypertension in adults with congenital heart disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "M.J. Schuuring" 1 => "B.J. Bouma" 2 => "R. Cordina" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2011.06.084" "Revista" => array:3 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2011" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21757243" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "K. Iversen" 1 => "A.S. Jensen" 2 => "T.V. Jensen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehq011" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2010" "volumen" => "31" "paginaInicial" => "1124" "paginaFinal" => "1131" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20202971" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ATS statement: guidelines for the six-minute walk test" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R.O. Crapo" 1 => "R. Casaburi" 2 => "A.L. Coates" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/ajrccm.166.1.at1102" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2002" "volumen" => "166" "paginaInicial" => "111" "paginaFinal" => "117" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12091180" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Eisenmenger syndrome: a clinical perspective in a new therapeutic era of pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Beghetti" 1 => "N. Galie" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jacc.2008.11.025" "Revista" => array:6 [ "tituloSerie" => "J Am Coll Cardiol" "fecha" => "2009" "volumen" => "53" "paginaInicial" => "733" "paginaFinal" => "740" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19245962" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe pulmonary hypertension without right ventricular failure: the unique hearts of patients with Eisenmenger syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "W. Hopkins" 1 => "A. Wagonner" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am Heart J" "fecha" => "2002" "volumen" => "89" "paginaInicial" => "34" "paginaFinal" => "38" ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pulmonary arterial hypertension in adults with congenital heart disease: distinct differences from other causes of pulmonary arterial hypertension and management implications" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "K. Dimopoulos" 1 => "G. Giannakoulas" 2 => "S.J. Worth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/HCO.0b013e3283126954" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Cardiol" "fecha" => "2008" "volumen" => "23" "paginaInicial" => "545" "paginaFinal" => "554" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18830068" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0085" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Atrial septal defects versus ventricular septal defects in BREATHE-5, a placebo-controlled study of pulmonary arterial hypertension related to Eisenmenger's syndrome: a subgroup analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R.M. Berger" 1 => "M. Beghetti" 2 => "N. Galie" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2009.04.037" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2010" "volumen" => "144" "paginaInicial" => "373" "paginaFinal" => "378" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19464064" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prolonged beneficial effect of bosentan treatment and 4-year survival rates in adult patients with pulmonary arterial hypertension associated with congenital heart disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J.C. Vis" 1 => "M.G. Duffels" 2 => "P. Mulder" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2011.06.064" "Revista" => array:3 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2011" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21757243" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0095" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "W.E. Hopkins" 1 => "L.L. Ochoa" 2 => "G.W. Richardson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Heart Lung Transplant" "fecha" => "1996" "volumen" => "15" "numero" => "1 Pt 1" "paginaInicial" => "100" "paginaFinal" => "105" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8820089" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0100" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "K. Dimopoulos" 1 => "R. Inuzuka" 2 => "S. Goletto" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCULATIONAHA.109.883876" "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "2010" "volumen" => "121" "paginaInicial" => "20" "paginaFinal" => "25" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20026774" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of bosentan for pulmonary arterial hypertension in adults with congenital heart disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "O. Monfredi" 1 => "L. Griffiths" 2 => "B. Clarke" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.amjcard.2011.07.006" "Revista" => array:6 [ "tituloSerie" => "Am J Cardiol" "fecha" => "2011" "volumen" => "108" "paginaInicial" => "1483" "paginaFinal" => "1488" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21943933" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0110" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/or the Eisenmenger syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "E.L. Tay" 1 => "A. Peset" 2 => "M. Papaphylactou" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2010.05.066" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2011" "volumen" => "151" "paginaInicial" => "307" "paginaFinal" => "312" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20580108" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:3 [ "identificador" => "xack45567" "titulo" => "Acknowledgement" "texto" => "We thank our nurses, Esmeralda Carvalho, Martiza Ribeiro and Sandra Mendes, for data collection." ] ] ] "idiomaDefecto" => "en" "url" => "/21742049/0000003200000002/v1_201305171228/S2174204913000433/v1_201305171228/en/main.assets" "Apartado" => array:4 [ "identificador" => "9917" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21742049/0000003200000002/v1_201305171228/S2174204913000433/v1_201305171228/en/main.pdf?idApp=UINPBA00004E&text.app=https://revportcardiol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204913000433?idApp=UINPBA00004E"]

Statistics

Original article

Long-term effect of bosentan in pulmonary hypertension associated with complex congenital heart disease

Efeito a longo-prazo do bosentano na hipertensão pulmonar associada a cardiopatias congénitas complexas

Rui Baptistaa,b,

Corresponding author

ruibaptista@gmail.com

Corresponding author.

, Graça Castroa, António Marinho da Silvaa, Pedro Monteiroa,b, Luís Augusto Providênciaa,b

a Unidade de Hipertensão Pulmonar, Serviço de Cardiologia, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

b Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal

Read

5694

Times
was read the article

1658

Total PDF

4036

Total HTML

Share statistics

 array:24 [
  "pii" => "S2174204913000433"
  "issn" => "21742049"
  "doi" => "10.1016/j.repce.2013.02.005"
  "estado" => "S300"
  "fechaPublicacion" => "2013-02-01"
  "aid" => "194"
  "copyright" => "Sociedade Portuguesa de Cardiologia"
  "copyrightAnyo" => "2012"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
  "subdocumento" => "fla"
  "cita" => "Rev Port Cardiol. 2013;32:123-9"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 3395
    "formatos" => array:3 [
      "EPUB" => 153
      "HTML" => 2593
      "PDF" => 649
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S2174204913000445"
    "issn" => "21742049"
    "doi" => "10.1016/j.repce.2013.02.006"
    "estado" => "S300"
    "fechaPublicacion" => "2013-02-01"
    "aid" => "206"
    "copyright" => "Sociedade Portuguesa de Cardiologia"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "fla"
    "cita" => "Rev Port Cardiol. 2013;32:131-7"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 4259
      "formatos" => array:3 [
        "EPUB" => 155
        "HTML" => 3420
        "PDF" => 684
      ]
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
      "titulo" => "Mitral valve replacement combined with coronary artery bypass graft surgery in patients with moderate-to-severe ischemic mitral regurgitation"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "pt"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "131"
          "paginaFinal" => "137"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "pt" => array:1 [
          "titulo" => "Substitui&#231;&#227;o da valva mitral combinada com cirurgia de revasculariza&#231;&#227;o do mioc&#225;rdio em pacientes com regurgita&#231;&#227;o mitral isqu&#233;mica moderada a grave"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "pt" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0010"
          "etiqueta" => "Figure 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 1236
              "Ancho" => 1597
              "Tamanyo" => 61087
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Improvement in left ventricular ejection fraction by echocardiography after surgery&#46; Values expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation&#46; CABG&#58; coronary artery bypass grafting&#59; MVR&#58; mitral valve replacement&#59; Postop&#58; postoperative&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Michel Pompeu B&#46;O&#46; S&#225;, Evelyn F&#46; Soares, Cec&#237;lia A&#46; Santos, Omar J&#46; Figueiredo, Renato O&#46;A&#46; Lima, Rodrigo R&#46; Escobar, Frederico P&#46; Vasconcelos, Ricardo C&#46; Lima"
          "autores" => array:8 [
            0 => array:2 [
              "nombre" => "Michel Pompeu B&#46;O&#46;"
              "apellidos" => "S&#225;"
            ]
            1 => array:2 [
              "nombre" => "Evelyn F&#46;"
              "apellidos" => "Soares"
            ]
            2 => array:2 [
              "nombre" => "Cec&#237;lia A&#46;"
              "apellidos" => "Santos"
            ]
            3 => array:2 [
              "nombre" => "Omar J&#46;"
              "apellidos" => "Figueiredo"
            ]
            4 => array:2 [
              "nombre" => "Renato O&#46;A&#46;"
              "apellidos" => "Lima"
            ]
            5 => array:2 [
              "nombre" => "Rodrigo R&#46;"
              "apellidos" => "Escobar"
            ]
            6 => array:2 [
              "nombre" => "Frederico P&#46;"
              "apellidos" => "Vasconcelos"
            ]
            7 => array:2 [
              "nombre" => "Ricardo C&#46;"
              "apellidos" => "Lima"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204913000445?idApp=UINPBA00004E"
    "url" => "/21742049/0000003200000002/v1_201305171228/S2174204913000445/v1_201305171228/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S2174204913000421"
    "issn" => "21742049"
    "doi" => "10.1016/j.repce.2013.02.004"
    "estado" => "S300"
    "fechaPublicacion" => "2013-02-01"
    "aid" => "210"
    "copyright" => "Sociedade Portuguesa de Cardiologia"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "fla"
    "cita" => "Rev Port Cardiol. 2013;32:117-22"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 3869
      "formatos" => array:3 [
        "EPUB" => 156
        "HTML" => 3094
        "PDF" => 619
      ]
    ]
    "en" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
      "titulo" => "High-sensitivity C-reactive protein predicts adverse outcomes after non-ST-segment elevation acute coronary syndrome regardless of GRACE risk score&#44; but not after ST-segment elevation myocardial infarction"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "pt"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "117"
          "paginaFinal" => "122"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "pt" => array:1 [
          "titulo" => "O valor do teste de alta sensibilidade da prote&#237;na C-reativa como preditor de resultados adversos em doentes com s&#237;ndrome coron&#225;ria aguda"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "pt" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0010"
          "etiqueta" => "Figure 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 1535
              "Ancho" => 1562
              "Tamanyo" => 67469
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Receiver operating characteristic curve for high-sensitivity C-reactive protein in predicting follow-up outcomes &#40;cardiac death and re-infarction&#41;&#46; Area under the curve&#58; 0&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Sergio Raposeiras Roub&#237;n, Cristina Barreiro Pardal, Filomena Roub&#237;n-Cami&#241;a, Raymundo Ocaranza Sanchez, Ezequiel &#193;lvarez Castro, Beatriz Paradela Dobarro, Jose Mar&#237;a Garc&#237;a-Acu&#241;a, Pablo Aguiar Souto, Michel Jacquet Hervet, Maria Jos&#233; Castrom&#225;n, Isabel Arufe, Bel&#233;n Outes, Mar&#237;a Victoria Reino-Maceiras, Emad Abu Assi, Jos&#233; Ram&#243;n Gonz&#225;lez-Juanatey"
          "autores" => array:15 [
            0 => array:2 [
              "nombre" => "Sergio"
              "apellidos" => "Raposeiras Roub&#237;n"
            ]
            1 => array:2 [
              "nombre" => "Cristina"
              "apellidos" => "Barreiro Pardal"
            ]
            2 => array:2 [
              "nombre" => "Filomena"
              "apellidos" => "Roub&#237;n-Cami&#241;a"
            ]
            3 => array:2 [
              "nombre" => "Raymundo"
              "apellidos" => "Ocaranza Sanchez"
            ]
            4 => array:2 [
              "nombre" => "Ezequiel"
              "apellidos" => "&#193;lvarez Castro"
            ]
            5 => array:2 [
              "nombre" => "Beatriz"
              "apellidos" => "Paradela Dobarro"
            ]
            6 => array:2 [
              "nombre" => "Jose Mar&#237;a"
              "apellidos" => "Garc&#237;a-Acu&#241;a"
            ]
            7 => array:2 [
              "nombre" => "Pablo"
              "apellidos" => "Aguiar Souto"
            ]
            8 => array:2 [
              "nombre" => "Michel"
              "apellidos" => "Jacquet Hervet"
            ]
            9 => array:2 [
              "nombre" => "Maria Jos&#233;"
              "apellidos" => "Castrom&#225;n"
            ]
            10 => array:2 [
              "nombre" => "Isabel"
              "apellidos" => "Arufe"
            ]
            11 => array:2 [
              "nombre" => "Bel&#233;n"
              "apellidos" => "Outes"
            ]
            12 => array:2 [
              "nombre" => "Mar&#237;a Victoria"
              "apellidos" => "Reino-Maceiras"
            ]
            13 => array:2 [
              "nombre" => "Emad"
              "apellidos" => "Abu Assi"
            ]
            14 => array:2 [
              "nombre" => "Jos&#233; Ram&#243;n"
              "apellidos" => "Gonz&#225;lez-Juanatey"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204913000421?idApp=UINPBA00004E"
    "url" => "/21742049/0000003200000002/v1_201305171228/S2174204913000421/v1_201305171228/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Long-term effect of bosentan in pulmonary hypertension associated with complex congenital heart disease"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "123"
        "paginaFinal" => "129"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Rui Baptista, Gra&#231;a Castro, Ant&#243;nio Marinho da Silva, Pedro Monteiro, Lu&#237;s Augusto Provid&#234;ncia"
        "autores" => array:5 [
          0 => array:4 [
            "nombre" => "Rui"
            "apellidos" => "Baptista"
            "email" => array:1 [
              0 => "ruibaptista&#64;gmail&#46;com"
            ]
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0005"
              ]
              2 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">¿</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Gra&#231;a"
            "apellidos" => "Castro"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Ant&#243;nio Marinho"
            "apellidos" => "da Silva"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Pedro"
            "apellidos" => "Monteiro"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Lu&#237;s Augusto"
            "apellidos" => "Provid&#234;ncia"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0005"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:2 [
          0 => array:3 [
            "entidad" => "Unidade de Hipertens&#227;o Pulmonar&#44; Servi&#231;o de Cardiologia&#44; Hospitais da Universidade de Coimbra&#44; Centro Hospitalar e Universit&#225;rio de Coimbra&#44; Coimbra&#44; Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">a</span>"
            "identificador" => "aff1"
          ]
          1 => array:3 [
            "entidad" => "Faculdade de Medicina&#44; Universidade de Coimbra&#44; Coimbra&#44; Portugal"
            "etiqueta" => "<span class="elsevierStyleSup">b</span>"
            "identificador" => "aff0005"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "pt" => array:1 [
        "titulo" => "Efeito a longo-prazo do bosentano na hipertens&#227;o pulmonar associada a cardiopatias cong&#233;nitas complexas"
      ]
    ]
    "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" => 896
            "Ancho" => 1472
            "Tamanyo" => 68568
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Effect of six months of bosentan therapy on WHO functional class&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Eisenmenger syndrome &#40;ES&#41; is defined as significant pulmonary arterial hypertension &#40;PAH&#41; in conjunction with congenital heart disease &#40;CHD&#41; and shunt reversal&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and comprises about 1&#37; of all CHD&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Although caused by a defect in the heart&#44; ES is a multiorgan disorder associated with numerous life-threatening complications&#44; including hemoptysis&#44; cerebrovascular accidents&#44; brain abscesses&#44; arrhythmias and syncope&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The majority of patients who develop ES survive to adulthood&#44; but markedly diminished exercise tolerance with reduced life expectancy is the rule&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Although their survival is better than in idiopathic pulmonary arterial hypertension &#40;IPAH&#41;&#44; ES patients share many histopathological similarities with IPAH&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">These similarities made the use of pulmonary vasodilators in this subset of patients an attractive option&#46; In the BREATHE-5 study&#44; the first placebo-controlled trial in patients with ES&#44; the endothelin-receptor antagonist &#40;ETRA&#41; bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and these results were further supported by the open-label extension of this pivotal trial&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> However&#44; BREATHE-5 only included ES patients with simple CHD &#40;atrial septal defect&#44; ventricular septal defect or both&#41;&#44; excluding patients with complex CHD&#44; patent ductus arteriosus or segmental pulmonary hypertension as in pulmonary atresia&#46; Evidence for the use of bosentan in this patient subset is only available in the form of series with small samples or short follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> Moreover&#44; due to the progressive nature of the disease&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> some patients may still have a negative evolution even though treated with advanced therapies&#44; highlighting the need for combination therapy&#46; In the only randomized controlled trial on combination therapy in ES&#44; the addition of sildenafil to ongoing bosentan failed to improve walking distance or pulmonary vascular resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The aims of our study were &#40;i&#41; to assess the safety of bosentan and its short-term effects on systemic oxygen saturation and exercise capacity in patients with complex CHD and PAH&#44; and &#40;ii&#41; to perform a long-term follow-up to assess efficacy and safety of bosentan treatment and the need for combination therapy in this group of complex CHD patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Participants</span><p id="par0020" class="elsevierStylePara elsevierViewall">We prospectively collected data on a dedicated database of all patients with PAH due to complex CHD&#44; who were being followed or were referred to our tertiary center between August 2003 and July 2009&#46; All patients had complex CHD&#44; with Eisenmenger physiology &#40;non-restrictive intra- or extracardiac communication with a right-to-left shunt at rest and high pulmonary vascular resistance&#41; or with severe PAH&#46; Right heart catheterization was performed in all patients to confirm the diagnosis before treatment initiation&#46; Patients with isolated atrial or ventricular septal defects were excluded from the analysis&#46; Functional class was II&#8211;IV in all participants&#44; assessed by the World Health Organization &#40;WHO&#41; classification&#46; All pulmonary vasodilator prescriptions were authorized by the pharmacy and this investigation conformed to the principles outlined in the Declaration of Helsinki&#46; The local ethics committee approved the research protocol and informed consent was obtained from all subjects&#46; Data up to May 2011 were analyzed&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Medication</span><p id="par0025" class="elsevierStylePara elsevierViewall">Bosentan treatment was initiated at a dose of 62&#46;5 mg bid&#46; After one month&#44; if no adverse effects occurred&#44; the dosage was doubled to 125 mg bid and maintained thereafter&#46; Baseline and monthly hemoglobin and liver function tests were obtained&#46; Treatment with prostanoids&#44; phosphodiesterase V inhibitors and other endothelin receptor antagonists was not allowed before the introduction of bosentan&#46; Based on patients&#8217; overall clinical assessment&#44; the team of attending physicians &#40;including a cardiologist with specialization in adult congenital heart disease &#91;GC&#93; and a pediatric cardiologist &#91;AMS&#93;&#41; was authorized to add sildenafil to the ongoing therapy in a starting dosage of 20 mg tid up to 50 mg tid&#46; All patients had a baseline iron status assessment and bosentan therapy was initiated only after correction of anemia and&#47;or iron deficiency&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Follow-up and final assessment</span><p id="par0030" class="elsevierStylePara elsevierViewall">Clinical follow-up was performed by a monthly clinical visit to our hospital in the first six months of treatment and in three-month periods thereafter&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Six-minute walking test</span><p id="par0035" class="elsevierStylePara elsevierViewall">Submaximal exercise capacity was assessed by the six-minute walking test &#40;6MWT&#41;&#46; This test was conducted by three experienced operators in a 30-m indoor marked corridor&#44; according to the guidelines of the American Thoracic Society&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Heart rate&#44; pulse oximetry and Borg dyspnea score were recorded at baseline and six minutes in all tests&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Continuous variables are expressed as means &#177; standard deviation and categorical variables by percentages&#46; Pairwise comparison between baseline and follow-up continuous variables was performed using the paired Student&#39;s t test&#46; Due to the small sample size&#44; all variables were tested for normality using the Kolmogorov-Smirnov test&#46; Categorical variables at baseline and follow-up were compared using Fisher&#39;s test&#46; All p-values were two-sided and a p-value less than 0&#46;05 was considered to indicate statistical significance&#46; Analyses and calculations were performed using SPSS version 13&#46;0 &#40;Chicago&#44; USA&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Baseline demographics and characteristics</span><p id="par0045" class="elsevierStylePara elsevierViewall">Patients&#8217; baseline characteristics are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Fourteen patients were enrolled in the treatment protocol&#46; Mean age was 37&#46;1&#177;11&#46;7 years and half of the patients were female&#46; The most common diagnosis was pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries &#40;35&#46;7&#37;&#41; &#40;one patient had a palliative Blalock-Taussig shunt&#41;&#44; followed by truncus arteriosus with ventricular septal defect &#40;28&#46;6&#37;&#41;&#44; patent ductus arteriosus with ventricular septal defect &#40;21&#46;4&#37;&#41; and transposition of the great arteries &#40;14&#46;3&#37;&#41; &#40;one patient underwent a Mustard procedure&#41;&#46; More than half of the patients were taking diuretics &#40;57&#46;1&#37;&#41; and six had an oxygen prescription&#59; no patient was taking warfarin&#46; At baseline&#44; all patients were normotensive &#40;mean 114&#177;17&#47;71&#177;24 mmHg&#41;&#44; with heart rates in the high normal range &#40;mean 88&#177;12 bpm&#41;&#46; Baseline hemoglobin was elevated &#40;17&#46;9&#177;2&#46;1 g&#47;dl&#41;&#59; all patients had normal liver function tests&#46; Hemodynamic findings were remarkable for a very high mean pulmonary artery systolic pressure &#40;79&#46;6&#177;31&#46;3 mmHg&#41;&#46; Regarding functional capacity&#44; more than 90&#37; of patients were in WHO class III or IV&#46; Only one patient was in WHO class II before starting bosentan&#46; No phlebotomies were conducted in the cohort&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Exposure to bosentan and need for combination therapy</span><p id="par0050" class="elsevierStylePara elsevierViewall">Median exposure to bosentan was 43 &#40;interquartile range 30-67&#41; months&#46; One patient discontinued bosentan after 16 months of usage due to low treatment adherence secondary to lower limb edema and was started on sildenafil&#46; During long-term follow-up&#44; four patients were started on sildenafil and one on triple combination therapy with intravenous iloprost due to progressive heart failure&#46; Sildenafil was added after a median bosentan treatment duration of 38 months&#46; Patients who needed combination therapy had a lower six-month 6MWT response after bosentan initiation &#40;&#43;22 m&#41; compared to patients who did not need therapeutic escalation during long-term follow-up &#40;&#43;85 m&#41;&#46; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> summarizes the data for each patient&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Exercise capacity and World Health Organization functional class</span><p id="par0055" class="elsevierStylePara elsevierViewall">After six months of bosentan treatment&#44; 6MWD increased in 12 and decreased two patients&#46; The mean increase in 6MWD was 56&#46;5 m&#44; from 371&#46;9&#177;90&#46;3 to 428&#46;4&#177;98&#46;3 m &#40;p&#61;0&#46;005&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Changes in functional class were significant&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#46; After a median follow-up of four years&#44; mean 6MWD for patients on bosentan monotherapy &#40;n&#61;8&#41; was 440&#46;1&#177;103&#46;8 m&#44; whereas for patients on bosentan-sildenafil combination therapy &#40;n&#61;4&#41; it was 428&#46;8&#177;96&#46;9 m &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Regarding functional class&#44; after a mean six months of treatment with bosentan&#44; nine patients were in class I or II and five patients remained in class III &#40;p&#61;0&#46;005&#41;&#46; No patient experienced worsening in functional class&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Results in patients with segmental pulmonary hypertension due to pulmonary atresia &#40;n&#61;5&#41; were similar to those of the overall population&#46; After six months&#44; mean 6MWD improved from 352&#46;6&#177;93&#46;2 m to 454&#46;0&#177;72&#46;7 m &#40;p&#61;0&#46;043&#41;&#46; The improvement in functional capacity was maintained at four years &#40;451&#46;8&#177;54&#46;7 m&#44; p&#61;0&#46;043 vs&#46; baseline and p&#61;0&#46;933 vs&#46; six months&#41;&#46; No differences were found regarding oxygen saturation pre- and post-exercise&#59; no patient required therapeutic escalation&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Safety&#44; morbidity and mortality</span><p id="par0065" class="elsevierStylePara elsevierViewall">One patient required discontinuation of bosentan due to lower limb edema&#46; No significant rise in liver transaminases was seen during follow-up and none of the patients had levels exceeding three times the upper limit of the reference range&#46; No signs of decreased oxygen saturation were seen&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Two patients &#40;14&#46;3&#37;&#41;&#44; both with truncus arteriosus&#44; died during follow-up after 48 months of vasodilator therapy&#46; One patient &#40;age 45&#41; on bosentan monotherapy died due to a complicated cerebral abscess&#46; The second patient &#40;age 48&#41;&#44; on triple combination therapy&#44; died of decompensated heart failure&#46; Survival rates in patients with complex CHD at one&#44; two and four years were 100&#37;&#44; 100&#37; and 85&#46;7&#37;&#44; respectively&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">In patients with PAH and complex CHD&#44; bosentan was a safe&#44; well tolerated and effective therapy&#46; The effects on 6MWT were evident after six months and were sustained in long-term follow-up&#46; The safety and drug tolerance were similar to those reported in the IPAH and BREATHE-5 studies&#44; with no serious side effects occurring during this long follow-up period&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Patients with PAH and complex CHD have a better long-term prognosis than those with IPAH&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> mainly due to preservation of biventricular function until the later stages of disease&#46; Some authors suggest that the right ventricle is &#8216;primed&#8217; for a lifetime of functioning at systemic level pressure&#44; with persistence of a protective fetal morphology&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Unfortunately&#44; and in contrast to previous claims that the hemodynamics of patients with ES was stable over time&#44; the BREATHE-5 study demonstrated that even in a limited 16-week follow-up&#44; indicators of progressive vascular disease&#44; such as pulmonary vascular resistance index&#44; worsened in the placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The available evidence regarding the use of disease-targeting therapies has recently been reviewed elsewhere&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The pivotal role of endothelin-1 in the development of pulmonary vasculopathy made the use of ETRA attractive and several studies&#44; including one randomized controlled trial&#44; established the benefit of ETRA in ES patients with simple defects&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5</span></a> The evidence for sildenafil or prostacyclins is based on smaller studies&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> However&#44; BREATHE-5 excluded patients with complex CHD and a recent single-center&#44; randomized placebo-controlled study with 21 patients had only one patient with complex disease&#46; Although it was thought that the location of the shunt &#40;pre-tricuspid versus post-tricuspid&#41; would influence treatment outcomes&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">16</span></a> a subgroup analysis of the BREATHE-5 study and two recent reports do not support this hypothesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;17</span></a> Moreover&#44; a comparison of patients with persistent PAH after shunt closure and ES patients found no differences in four-year survival&#46;<a class="elsevierStyleCrossRef" href="#bib17"><span class="elsevierStyleSup">17</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">After the use of bosentan&#44; we noted a significant improvement in exercise capacity and in WHO functional class&#44; with no decrease in Borg dyspnea score&#44; indicating that these patients increased their exercise capacity with a similar level of perceived dyspnea&#46; Moreover&#44; mean six-month improvement in 6MWD was 56 m&#44; similar to other reports&#44; including patients with non-complex disease<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and with IPAH&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Our results reproduce&#44; in a larger population&#44; the findings of Diaz-Caraballo et al&#46;&#44; the only study to date focusing solely on complex congenital heart disease&#46; In that study&#44; mean 6MWD improved significantly at six months &#40;from 266&#177;161 to 343&#177;121 m&#44; p&#61;0&#46;045&#41;&#44; the change being maintained at two years&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> We extend these findings to a four-year follow-up&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">We also included pulmonary atresia patients&#44; a distinct subgroup&#44; as they present with segmental pulmonary hypertension and no shunt reversal&#46; Little evidence is available regarding the role of pulmonary vasodilators in these patients&#46; A recent report by Schuuring et al&#46; on seven patients demonstrates a 62-m improvement in 6MWD after one year of bosentan treatment&#46;<a class="elsevierStyleCrossRef" href="#bib10"><span class="elsevierStyleSup">10</span></a> Our results are similar&#44; with a significant improvement in walking distance at six months&#44; sustained in the long term&#46; Interestingly&#44; none of the patients needed combination therapy&#46; The mechanism whereby bosentan acts on this subset of patients is not known&#44; but may be related to its action on the endothelin pathway&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Although not evidence-based but in line with recommendations for IPAH&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> combination therapy with sildenafil was initiated in four patients due to disease progression&#44; reflecting the high-risk group that was studied and the progressive nature of the disease during long-term follow-up&#46; It is noteworthy that the four patients who underwent therapeutic escalation remained clinically stable for almost four years before the initiation of sildenafil&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Patients with PAH and complex CHD are at high risk of death<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">18</span></a> but there is a paucity of data regarding survival in such patients under vasodilator therapy&#46; In our cohort&#44; total mortality was 14&#37; at four years&#44; which is higher than in the series by Dimopoulos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">19</span></a> &#40;around 3&#37; at two years&#41;&#44; lower than that reported by Vis et al&#46;<a class="elsevierStyleCrossRef" href="#bib17"><span class="elsevierStyleSup">17</span></a> &#40;20&#37; at four years&#41;&#44; but similar to the recently published results by Monfredi et al&#46;<a class="elsevierStyleCrossRef" href="#bib20"><span class="elsevierStyleSup">20</span></a> Differences in study design&#44; follow-up duration and population selection may be responsible for these disparities&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The safety of bosentan in this high-risk population was remarkable&#46; No patient experienced a rise in liver enzymes exceeding three times the upper limit of normal or systemic hypotension&#46; Only one patient discontinued bosentan due to lower limb edema&#46; Moreover&#44; and in line with previous reports&#44; no changes were noted in systemic oxygenation&#46; This may be due to the limited influence of bosentan on the net right-to-left shunt because its effects on both pulmonary and systemic vascular resistance are similar&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">This was a non-randomized&#44; single-center study&#44; with a limited number of patients reflecting the rarity of this condition&#46; It represents a cohort of patients being followed in a specialized pulmonary hypertension clinic&#46; Our small sample precludes further comparisons between different types of congenital defects&#46; Although only patients with right heart catheterization-confirmed pulmonary hypertension were included in this study&#44; the heterogeneity of the congenital lesions causing it may have influenced clinical evolution&#44; themselves affecting the outcome&#46; An example is truncal valve regurgitation in truncus arteriosus patients&#59; both patients who died had severe regurgitation that may have contributed to their dismal prognosis&#46; Several factors can influence exercise capacity in ES patients&#44; including iron status&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">21</span></a> associated cardiac lesions or pulmonary comorbidities&#59; however&#44; our results regarding exercise capacity and functional status were consistent with other studies in patients without complex congenital disease&#44; suggesting that bosentan has a true therapeutic effect&#59; all patients had regular iron status assessments and correction as needed&#46; We did not perform hemodynamic re-evaluation of patients after pulmonary vasodilator therapy&#59; all clinical decisions regarding therapeutic escalation were made in the light of clinical&#44; laboratorial&#44; echocardiographic and functional data&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0120" class="elsevierStylePara elsevierViewall">Bosentan was safe and was associated with improved exercise capacity in patients with complex congenital heart disease and PAH&#46; The improvement in exercise capacity was maintained up to four years and the longer-term safety profile was similar to that reported in simple congenital heart disease patients&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">Gra&#231;a Castro and Ant&#243;nio Marinho da Silva are consultants for Actelion Portugal&#46; Rui Baptista has received funding for research from Actelion Portugal&#46; Pedro Monteiro and Lu&#237;s Augusto Provid&#234;ncia have no relationships relevant to the contents of this paper to disclose&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:12 [
        0 => array:2 [
          "identificador" => "xres177659"
          "titulo" => array:6 [
            0 => "Abstract"
            1 => "Background"
            2 => "Objectives"
            3 => "Methods"
            4 => "Results"
            5 => "Conclusions"
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec166312"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xres177658"
          "titulo" => array:6 [
            0 => "Resumo"
            1 => "Introdu&#231;&#227;o"
            2 => "Objectivos"
            3 => "M&#233;todos"
            4 => "Resultados"
            5 => "Conclus&#245;es"
          ]
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec166313"
          "titulo" => "Palavras chave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Methods"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Participants"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Medication"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Follow-up and final assessment"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Six-minute walking test"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0040"
          "titulo" => "Results"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Baseline demographics and characteristics"
            ]
            1 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Exposure to bosentan and need for combination therapy"
            ]
            2 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Exercise capacity and World Health Organization functional class"
            ]
            3 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Safety&#44; morbidity and mortality"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conclusions"
        ]
        9 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Conflicts of interest"
        ]
        10 => array:2 [
          "identificador" => "xack45567"
          "titulo" => "Acknowledgement"
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2012-01-17"
    "fechaAceptado" => "2012-02-13"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec166312"
          "palabras" => array:3 [
            0 => "Bosentan"
            1 => "Congenital heart disease"
            2 => "Pulmonary hypertension"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras chave"
          "identificador" => "xpalclavsec166313"
          "palabras" => array:3 [
            0 => "Bosentan"
            1 => "Cardiopatia cong&#233;nita"
            2 => "Hipertens&#227;o pulmonar"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bosentan is recommended for symptomatic patients with Eisenmenger syndrome due to simple congenital lesions such as atrial and ventricular septal defects &#40;VSD&#41;&#46; However&#44; its long-term efficacy and safety in patients with pulmonary arterial hypertension &#40;PAH&#41; associated with complex congenital heart disease &#40;CHD&#41; is unknown&#46;</p> <span class="elsevierStyleSectionTitle">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We examined the short- and long-term effects and safety profile of bosentan in patients with PAH and complex CHD&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We followed 14 patients with PAH and complex CHD for a mean of four years&#46; Demographic parameters&#44; exercise capacity assessed by the six-minute walking test &#40;6MWT&#41; and oxygen saturation were assessed at baseline&#44; six months and at follow-up&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Mean age was 37&#46;1&#177;11&#46;7 years&#59; 90&#37; were in WHO class III or IV&#46; The most common diagnosis was pulmonary atresia with VSD &#40;35&#46;7&#37;&#41;&#44; followed by truncus arteriosus &#40;28&#46;6&#37;&#41;&#44; patent ductus arteriosus &#40;21&#46;4&#37;&#41; and transposition of the great arteries &#40;14&#46;3&#37;&#41;&#46; After six months of treatment&#44; six-minute walking distance &#40;6MWD&#41; increased from 371&#46;9 to 428&#46;4 m &#40;p&#61;0&#46;005&#41; and functional class was improved &#40;p&#61;0&#46;005&#41;&#46; After four years&#44; one patient discontinued bosentan due to side effects and four patients were started on sildenafil&#44; after a mean 38 months of bosentan treatment&#46; Mean 6MWD for patients on bosentan monotherapy &#40;n&#61;8&#41; was 440&#46;1&#177;103&#46;8 m&#44; whereas for patients on bosentan-sildenafil combination therapy &#40;n&#61;4&#41; it was 428&#46;8&#177;96&#46;9 m&#44; after four years of therapy&#46; Two patients died during follow-up&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Bosentan was safe and was associated with improved exercise capacity in patients with PAH and complex CHD&#46; This improvement was sustained for up to four years and the safety profile was similar to simple CHD patients&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introdu&#231;&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">O bosentano &#233; recomendado em doentes com hipertens&#227;o arterial pulmonar &#40;HAP&#41; associada a les&#245;es cong&#233;nitas simples&#44; como comunica&#231;&#245;es interventriculares &#40;CIV&#41;&#46; Contudo&#44; a sua efic&#225;cia e seguran&#231;a a longo prazo em doentes com HAP associada a cardiopatias cong&#233;nitas complexas &#40;HAP-CCC&#41; &#233; desconhecida&#46;</p> <span class="elsevierStyleSectionTitle">Objectivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Avali&#225;mos a efic&#225;cia e seguran&#231;a a curto e longo-prazo do bosentano na HAP-CCC&#46;</p> <span class="elsevierStyleSectionTitle">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Estudaram-se 14 doentes com HAP-CCC&#44; relativamente a par&#226;metros demogr&#225;ficos&#44; capacidade funcional avaliada pelo teste de marcha de seis minutos &#40;TM6M&#41; e satura&#231;&#227;o de oxig&#233;nio&#44; antes de iniciar terap&#234;utica&#44; aos seis meses e durante o per&#237;odo de seguimento cl&#237;nico a longo-prazo &#40;quatro anos&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Noventa por cento dos doentes encontravam-se em classe OMS III ou IV&#44; com idade m&#233;dia de 37&#44;1 &#177; 11&#44;7 anos&#46; O diagn&#243;stico mais frequente foi a atr&#233;sia pulmonar com CIV &#40;35&#44;7&#37;&#41;&#44; seguida de <span class="elsevierStyleItalic">truncus arteriosus</span> &#40;28&#44;6&#37;&#41;&#44; canal arterial patente &#40;21&#44;4&#37;&#41; e transposi&#231;&#227;o de grandes vasos &#40;14&#44;3&#37;&#41;&#46; Ap&#243;s seis meses de tratamento&#44; o TM6M aumentou de 371&#44;9 para 428&#44;4 metros &#40;p &#61; 0&#44;005&#41; e a classe funcional melhorou &#40;p &#61; 0&#44;005&#41;&#46; Ap&#243;s quatro anos&#44; um doente suspendeu bosentano devido a efeitos secund&#225;rios e quatro doentes iniciaram sildenafil&#44; ap&#243;s uma dura&#231;&#227;o m&#233;dia de monoterapia de 38 meses&#46; Ap&#243;s quatro anos de terap&#234;utica&#44; nos doentes em monoterapia com bosentano &#40;n &#61; 8&#41; o TM6M foi de 440&#44;1 &#177; 103&#44;8 metros&#44; enquanto que nos doentes com bosentano-sildenafil &#40;n &#61; 4&#41; foi de 428&#44;8 &#177; 96&#44;9 metros&#46; Dois doentes faleceram durante o per&#237;odo de seguimento cl&#237;nico&#46;</p> <span class="elsevierStyleSectionTitle">Conclus&#245;es</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">O bosentano foi seguro e esteve associado a melhoria na capacidade funcional em doentes com HAP-CCC at&#233; aos quatro anos de seguimento cl&#237;nico&#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" => 896
            "Ancho" => 1472
            "Tamanyo" => 68568
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Effect of six months of bosentan therapy on WHO functional class&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Clinical characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">n&#61;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Age&#44; years</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;1&#177;11&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Female gender&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Diagnosis</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Truncus arteriosus&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;28&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Transposition of the great arteries&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;14&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pulmonary atresia with ventricular septal defect&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;35&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patent ductus arteriosus&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;21&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Medications</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Warfarin&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Digoxin&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;21&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Diuretics&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;57&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Mean daily furosemide dosage &#40;mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Beta-blockers&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;7&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Oxygen&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;42&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Laboratory variables</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hemoglobin&#44; g&#47;dl</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;9&#177;2&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mean corpuscular volume&#44; fl</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">89&#46;0&#177;5&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Creatinine&#44; mg g&#47;dl</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8&#177;0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Alanine aminotransferase&#44; U&#47;l</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;4&#177;4&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Hemodynamic variables</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mean pulmonary artery pressure&#44; mmHg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&#46;6&#177;31&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab272096.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">O<span class="elsevierStyleInf">2</span> Sat&#58; oxygen saturation&#59; SBP&#58; systolic blood pressure&#46; WHO&#58; World Health Organization functional class&#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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Baselinen&#61;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">6 monthsn&#61;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mean difference &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Heart rate&#44; beats&#47;min</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">88&#177;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90&#177;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;&#8722;5-9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;765&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Systolic blood pressure&#44; mmHg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">114&#177;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">119&#177;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;&#8722;3-13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;170&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Diastolic blood pressure&#44; mmHg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&#177;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#177;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;12 &#40;&#8722;28-4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">WHO class</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>I&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;7&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>II&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;7&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;57&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>III&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11 &#40;78&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;35&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>IV&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;14&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;895&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Six-minute walking distance&#44; m</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">371&#46;9&#177;90&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">428&#46;4&#177;98&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#46;5 &#40;14&#46;3-98&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Systemic O</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">Sat at rest&#44; &#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">82&#46;0&#177;6&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&#46;9&#177;6&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;1 &#40;&#8722;2&#46;7-2&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;956&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Systemic O</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">Sat at peak exercise&#44; &#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">73&#46;4&#177;13&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#46;8&#177;10&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;0&#46;6 &#40;&#8722;5&#46;1-6&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;832&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Peak SBP&#44; mmHg</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">123&#177;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">130&#177;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;0 &#40;&#8722;0&#46;3-14&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;058&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Borg dyspnea score&#44; baseline</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;4&#177;1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;3&#177;2&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;9 &#40;&#8722;0&#46;8-2&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;271&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Borg dyspnea score after exercise</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;7&#177;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;5&#177;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8 &#40;&#8722;0&#46;2-1&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;108&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab272095.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Clinical characteristics at baseline and six months after bosentan therapy&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">6MWD&#58; six-minute walking distance&#44; in m&#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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Follow-up timePatients on bosentan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baselinen&#61;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Six monthsn&#61;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Three yearsn&#61;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Four yearsn&#61;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p&#40;trend&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6MWD&#44; m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">371&#46;9&#177;90&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">428&#46;4&#177;98&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">439&#46;5&#177;97&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">440&#46;1&#177;103&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab272094.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Long-term effect of bosentan monotherapy on exercise capacity&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">DOB&#58; date of birth&#59; F&#58; female&#59; M&#58; male&#59; PDA&#58; patent ductus arteriosus&#59; RHF&#58; right heart failure&#59; 6M&#58; six-month&#59; 6MWD&#58; six-minute walking distance&#44; in m&#59; TA&#58; truncus arteriosus&#59; TGA&#58; transposition of the great arteries&#59; VSD&#58; ventricular septal defect&#59; WHO&#58; World Health Organization functional class&#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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">DOB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Vital status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">WHO initial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">6MWT initial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Bosentan start date&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">WHO6M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">6MWT6M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Sildenafil start date&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">6MWT prior&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">6MWD6M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">WHO6M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Date of death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Cause of death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13 Jan 63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDA and VSD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">258&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Jun 04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">218&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aug 08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">370&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">392&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 Jun 70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">517&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Jan 07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">550&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feb 10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">540&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29 Aug 93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDA and VSD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">441&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aug 03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">490&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feb 10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">410&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">468&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22 Jul 61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deceased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">324&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aug 05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">370&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Apr 08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">180&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aug 09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab272093.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Individual data for patients that required therapeutic escalation&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:21 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Wood"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br Med J"
                        "fecha" => "1958"
                        "volumen" => "2"
                        "paginaInicial" => "755"
                        "paginaFinal" => "762"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/519181"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary arterial hypertension in congenital heart disease&#58; an epidemiologic perspective from a Dutch registry"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46;G&#46; Duffels"
                            1 => "P&#46;M&#46; Engelfriet"
                            2 => "R&#46;M&#46; Berger"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2006.09.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2007"
                        "volumen" => "120"
                        "paginaInicial" => "198"
                        "paginaFinal" => "204"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17182132"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "ESC guidelines for the management of grown-up congenital heart disease &#40;new version 2010&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "H&#46; Baumgartner"
                            1 => "P&#46; Bonhoeffer"
                            2 => "N&#46;M&#46; De Groot"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehq249"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2010"
                        "volumen" => "31"
                        "paginaInicial" => "2915"
                        "paginaFinal" => "2957"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20801927"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Poor prognosis and related factors in adults with Eisenmenger syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "H&#46; Oya"
                            1 => "N&#46; Nagaya"
                            2 => "M&#46; Uematsu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am Heart J"
                        "fecha" => "2002"
                        "volumen" => "143"
                        "paginaInicial" => "739"
                        "paginaFinal" => "744"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11923814"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Guidelines for the diagnosis and treatment of pulmonary hypertension&#58; the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology &#40;ESC&#41; and the European Respiratory Society &#40;ERS&#41;&#44; endorsed by the International Society of Heart and Lung Transplantation &#40;ISHLT&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "N&#46; Galie"
                            1 => "M&#46;M&#46; Hoeper"
                            2 => "M&#46; Humbert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehp297"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2009"
                        "volumen" => "30"
                        "paginaInicial" => "2493"
                        "paginaFinal" => "2537"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19713419"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bosentan therapy in patients with Eisenmenger syndrome&#58; a multicenter&#44; double-blind&#44; randomized&#44; placebo-controlled study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "N&#46; Galie"
                            1 => "M&#46; Beghetti"
                            2 => "M&#46;A&#46; Gatzoulis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.106.630715"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2006"
                        "volumen" => "114"
                        "paginaInicial" => "48"
                        "paginaFinal" => "54"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16801459"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome&#58; results of the BREATHE-5 open-label extension study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46;A&#46; Gatzoulis"
                            1 => "M&#46; Beghetti"
                            2 => "N&#46; Galie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2007.04.078"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2008"
                        "volumen" => "127"
                        "paginaInicial" => "27"
                        "paginaFinal" => "32"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17658633"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term bosentan treatment of complex congenital heart disease and Eisenmenger&#39;s syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "E&#46; Diaz-Caraballo"
                            1 => "A&#46;E&#46; Gonzalez-Garcia"
                            2 => "M&#46; Renones"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Esp Cardiol"
                        "fecha" => "2009"
                        "volumen" => "62"
                        "paginaInicial" => "1046"
                        "paginaFinal" => "1049"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19712626"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The efficacy and safety of sildenafil in patients with pulmonary arterial hypertension associated with the different types of congenital heart disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "W&#46;-J&#46; Zeng"
                            1 => "X&#46;-L&#46; Lu"
                            2 => "C&#46;-M&#46; Xiong"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/clc.20917"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Cardiol"
                        "fecha" => "2011"
                        "volumen" => "34"
                        "paginaInicial" => "513"
                        "paginaFinal" => "518"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21678455"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of segmental pulmonary artery hypertension in adults with congenital heart disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "M&#46;J&#46; Schuuring"
                            1 => "B&#46;J&#46; Bouma"
                            2 => "R&#46; Cordina"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2011.06.084"
                      "Revista" => array:3 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2011"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21757243"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combination therapy with bosentan and sildenafil in Eisenmenger syndrome&#58; a randomized&#44; placebo-controlled&#44; double-blinded trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "K&#46; Iversen"
                            1 => "A&#46;S&#46; Jensen"
                            2 => "T&#46;V&#46; Jensen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehq011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2010"
                        "volumen" => "31"
                        "paginaInicial" => "1124"
                        "paginaFinal" => "1131"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20202971"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "ATS statement&#58; guidelines for the six-minute walk test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "R&#46;O&#46; Crapo"
                            1 => "R&#46; Casaburi"
                            2 => "A&#46;L&#46; Coates"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.166.1.at1102"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2002"
                        "volumen" => "166"
                        "paginaInicial" => "111"
                        "paginaFinal" => "117"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12091180"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Eisenmenger syndrome&#58; a clinical perspective in a new therapeutic era of pulmonary arterial hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Beghetti"
                            1 => "N&#46; Galie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2008.11.025"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2009"
                        "volumen" => "53"
                        "paginaInicial" => "733"
                        "paginaFinal" => "740"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19245962"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe pulmonary hypertension without right ventricular failure&#58; the unique hearts of patients with Eisenmenger syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "W&#46; Hopkins"
                            1 => "A&#46; Wagonner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am Heart J"
                        "fecha" => "2002"
                        "volumen" => "89"
                        "paginaInicial" => "34"
                        "paginaFinal" => "38"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary arterial hypertension in adults with congenital heart disease&#58; distinct differences from other causes of pulmonary arterial hypertension and management implications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "K&#46; Dimopoulos"
                            1 => "G&#46; Giannakoulas"
                            2 => "S&#46;J&#46; Worth"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/HCO.0b013e3283126954"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Cardiol"
                        "fecha" => "2008"
                        "volumen" => "23"
                        "paginaInicial" => "545"
                        "paginaFinal" => "554"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18830068"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Atrial septal defects versus ventricular septal defects in BREATHE-5&#44; a placebo-controlled study of pulmonary arterial hypertension related to Eisenmenger&#39;s syndrome&#58; a subgroup analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "R&#46;M&#46; Berger"
                            1 => "M&#46; Beghetti"
                            2 => "N&#46; Galie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2009.04.037"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2010"
                        "volumen" => "144"
                        "paginaInicial" => "373"
                        "paginaFinal" => "378"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19464064"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prolonged beneficial effect of bosentan treatment and 4-year survival rates in adult patients with pulmonary arterial hypertension associated with congenital heart disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "J&#46;C&#46; Vis"
                            1 => "M&#46;G&#46; Duffels"
                            2 => "P&#46; Mulder"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2011.06.064"
                      "Revista" => array:3 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2011"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21757243"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "W&#46;E&#46; Hopkins"
                            1 => "L&#46;L&#46; Ochoa"
                            2 => "G&#46;W&#46; Richardson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "J Heart Lung Transplant"
                        "fecha" => "1996"
                        "volumen" => "15"
                        "numero" => "1 Pt 1"
                        "paginaInicial" => "100"
                        "paginaFinal" => "105"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8820089"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "K&#46; Dimopoulos"
                            1 => "R&#46; Inuzuka"
                            2 => "S&#46; Goletto"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.109.883876"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2010"
                        "volumen" => "121"
                        "paginaInicial" => "20"
                        "paginaFinal" => "25"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20026774"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy and safety of bosentan for pulmonary arterial hypertension in adults with congenital heart disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "O&#46; Monfredi"
                            1 => "L&#46; Griffiths"
                            2 => "B&#46; Clarke"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.amjcard.2011.07.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Cardiol"
                        "fecha" => "2011"
                        "volumen" => "108"
                        "paginaInicial" => "1483"
                        "paginaFinal" => "1488"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21943933"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and&#47;or the Eisenmenger syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "E&#46;L&#46; Tay"
                            1 => "A&#46; Peset"
                            2 => "M&#46; Papaphylactou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijcard.2010.05.066"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cardiol"
                        "fecha" => "2011"
                        "volumen" => "151"
                        "paginaInicial" => "307"
                        "paginaFinal" => "312"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20580108"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:3 [
        "identificador" => "xack45567"
        "titulo" => "Acknowledgement"
        "texto" => "<p id="par0130" class="elsevierStylePara elsevierViewall">We thank our nurses&#44; Esmeralda Carvalho&#44; Martiza Ribeiro and Sandra Mendes&#44; for data collection&#46;</p>"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/21742049/0000003200000002/v1_201305171228/S2174204913000433/v1_201305171228/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "9917"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original Articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/21742049/0000003200000002/v1_201305171228/S2174204913000433/v1_201305171228/en/main.pdf?idApp=UINPBA00004E&text.app=https://revportcardiol.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204913000433?idApp=UINPBA00004E"
]

Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2013.02.005

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	4	5	9
2024 October	33	19	52
2024 September	45	27	72
2024 August	38	26	64
2024 July	20	23	43
2024 June	25	22	47
2024 May	25	12	37
2024 April	20	25	45
2024 March	40	22	62
2024 February	24	34	58
2024 January	19	27	46
2023 December	29	27	56
2023 November	19	16	35
2023 October	16	26	42
2023 September	18	19	37
2023 August	16	17	33
2023 July	47	6	53
2023 June	19	9	28
2023 May	26	16	42
2023 April	11	7	18
2023 March	18	16	34
2023 February	17	15	32
2023 January	14	5	19
2022 December	22	19	41
2022 November	30	15	45
2022 October	25	22	47
2022 September	21	24	45
2022 August	30	30	60
2022 July	22	20	42
2022 June	18	19	37
2022 May	18	30	48
2022 April	18	17	35
2022 March	18	22	40
2022 February	24	15	39
2022 January	17	16	33
2021 December	14	19	33
2021 November	24	34	58
2021 October	29	42	71
2021 September	19	33	52
2021 August	22	25	47
2021 July	15	31	46
2021 June	13	3	16
2021 May	26	28	54
2021 April	37	28	65
2021 March	44	14	58
2021 February	67	9	76
2021 January	19	13	32
2020 December	25	9	34
2020 November	20	11	31
2020 October	17	4	21
2020 September	38	5	43
2020 August	15	0	15
2020 July	38	6	44
2020 June	30	5	35
2020 May	35	3	38
2020 April	42	9	51
2020 March	45	6	51
2020 February	40	12	52
2020 January	25	6	31
2019 December	21	5	26
2019 November	30	9	39
2019 October	41	2	43
2019 September	14	9	23
2019 August	18	9	27
2019 July	31	9	40
2019 June	23	5	28
2019 May	30	9	39
2019 April	28	9	37
2019 March	34	7	41
2019 February	50	7	57
2019 January	16	8	24
2018 December	23	6	29
2018 November	112	6	118
2018 October	232	14	246
2018 September	69	10	79
2018 August	38	13	51
2018 July	25	2	27
2018 June	39	8	47
2018 May	43	5	48
2018 April	46	6	52
2018 March	43	7	50
2018 February	24	2	26
2018 January	30	3	33
2017 December	54	11	65
2017 November	34	16	50
2017 October	40	12	52
2017 September	29	10	39
2017 August	32	8	40
2017 July	19	8	27
2017 June	29	6	35
2017 May	45	6	51
2017 April	32	4	36
2017 March	35	30	65
2017 February	22	2	24
2017 January	22	1	23
2016 December	34	12	46
2016 November	20	1	21
2016 October	35	3	38
2016 September	18	7	25
2016 August	5	1	6
2016 July	6	3	9
2016 June	9	1	10
2016 May	8	5	13
2016 April	14	1	15
2016 March	19	11	30
2016 February	31	17	48
2016 January	20	14	34
2015 December	29	7	36
2015 November	14	4	18
2015 October	22	10	32
2015 September	30	8	38
2015 August	21	7	28
2015 July	20	4	24
2015 June	8	3	11
2015 May	24	4	28
2015 April	29	18	47
2015 March	14	6	20
2015 February	13	3	16
2015 January	27	4	31
2014 December	33	4	37
2014 November	16	7	23
2014 October	18	4	22
2014 September	22	4	26
2014 August	26	5	31
2014 July	23	11	34
2014 June	26	3	29
2014 May	17	6	23
2014 April	14	5	19
2014 March	34	12	46
2014 February	29	6	35
2014 January	40	14	54
2013 December	27	8	35
2013 November	32	12	44
2013 October	28	9	37
2013 September	31	15	46
2013 August	33	17	50
2013 July	34	13	47
2013 June	25	6	31
2013 May	22	7	29
2013 April	43	16	59
2013 March	35	11	46

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter