Update on pulmonary arterial hypertension

Mejía Chew, C.R.; Batres, S.A.; Ríos Blanco, J.J.

doi:10.1016/j.rceng.2016.05.001

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(A) Obtaining an ultrasound longitudinal image of the femoral cartilage. (B) Healthy patient; the lower line corresponds to the cortical bone touching the hyaline cartilage. The upper line corresponds to the surface of the hyaline cartilage exposed to the synovial liquid. (C) Double contour sign in the patient with asymptomatic hyperuricemia described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. The upper hyperechoic line is due to the MUS deposit on the hyaline cartilage. (D) Ultrasound longitudinal image of the first metatarsophalangeal joint in the patient with gout, apparently not tophaceous, described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. (E) Irregular hyperechoic line (arrows) corresponding to the cortical bone. A hyperechoic cloudy area (line of points) can be observed and is due to the MUS deposit (tophus). An anechoic surrounding halo (points of arrows) can be observed. (F) Doppler signal (“Christmas tree”) suggestive of significant inflammatory response." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. García Puig, L. Beltrán, C. Mejía Chew, R. Torres, D. Tebar Márquez, A. Pose Reino" "autores" => array:6 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "García Puig" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Beltrán" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "Mejía Chew" ] 3 => array:2 [ "nombre" => "R." "apellidos" => "Torres" ] 4 => array:2 [ "nombre" => "D." "apellidos" => "Tebar Márquez" ] 5 => array:2 [ "nombre" => "A." "apellidos" => "Pose Reino" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256516300807" "doi" => "10.1016/j.rce.2016.05.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300807?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887416300327?idApp=WRCEE" "url" => "/22548874/0000021600000008/v1_201610290712/S2254887416300327/v1_201610290712/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2254887416300339" "issn" => "22548874" "doi" => "10.1016/j.rceng.2016.06.005" "estado" => "S300" "fechaPublicacion" => "2016-11-01" "aid" => "1284" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Rev Clin Esp. 2016;216:427-35" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 6 "formatos" => array:2 [ "HTML" => 2 "PDF" => 4 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Pleural ultrasound for clinicians" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "427" "paginaFinal" => "435" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Ecografía pleural para clínicos" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 1798 "Ancho" => 2502 "Tamanyo" => 375221 ] ] "descripcion" => array:1 [ "en" => "Pleural fluid echogenicity patterns: anechoic ((A): arrows indicating thickening of the diaphragm with a malignant cause), complex non-septated ((B): arrowheads indicating various echogenic points, and the arrow indicating a malignant diaphragmatic node) complex septated (C) and homogeneously echogenic ((D): hemothorax)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.M. Porcel" "autores" => array:1 [ 0 => array:2 [ "nombre" => "J.M." "apellidos" => "Porcel" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0014256516300820" "doi" => "10.1016/j.rce.2016.05.009" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0014256516300820?idApp=WRCEE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887416300339?idApp=WRCEE" "url" => "/22548874/0000021600000008/v1_201610290712/S2254887416300339/v1_201610290712/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Update on pulmonary arterial hypertension" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "436" "paginaFinal" => "444" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "C.R. Mejía Chew, S.A. Batres, J.J. Ríos Blanco" "autores" => array:3 [ 0 => array:4 [ "nombre" => "C.R." "apellidos" => "Mejía Chew" "email" => array:1 [ 0 => "carlos_mejiachew@yahoo.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "S.A." "apellidos" => "Batres" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J.J." "apellidos" => "Ríos Blanco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Grupo Hipertensión Pulmonar La Paz (GRUHPAZ), Servicio de Medicina Interna, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Grupo Hipertensión Pulmonar La Paz (GRUHPAZ), Servicio de Neumología, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización en hipertensión arterial pulmonar" ] ] "textoCompleto" => "BackgroundPulmonary hypertension (HP) is classified into 5 groups according to the histopathological findings and hemodynamic profiles, which involve a common therapeutic strategy.Pulmonary arterial hypertension (PAH), which corresponds to group 1 of the classification, is a rare (5 cases per million individuals) and progressive disease of the pulmonary vasculature that mainly affects the pulmonary arterioles (precapillary), regardless of the triggering etiology. Without treatment, PAH has an ominous prognosis, with a mean survival similar to that of patients with metastatic breast cancer (i.e., stage III).<a class="elsevierStyleCrossRef" href="#bib0235">2</a>In recent years, there have been significant therapeutic developments in HP, which have been collected in very recently published European guidelines.<a class="elsevierStyleCrossRefs" href="#bib0240">3,4</a> This article is a clinical update mainly on PAH, and its objective is to provide an update on the knowledge and developments of the pathogenesis, diagnosis and treatment of this disease, from a practical perspective for clinicians.DefinitionsThe diagnosis of PAH is based on hemodynamic criteria and therefore requires the implementation of right cardiac catheterization. The hemodynamic parameters that need to be present for the diagnosis are as follows:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.Mean pulmonary artery pressure (mPAP) ≥25mmHg.</li><li class="elsevierStyleListItem" id="lsti0010">2.Pulmonary capillary wedge pressure (PCWP) ≤15mmHg.</li><li class="elsevierStyleListItem" id="lsti0015">3.Pulmonary vascular resistance >3 Wood units.<a class="elsevierStyleCrossRef" href="#bib0250">5</a></li></ul>These measurements are performed at rest. The exercise-induced increase in mPAP increases with age and lacks a universal cutoff that can be used for defining PAH according to the mPAP measured after physical effort.The latest European guidelines also recommend the measurement of the diastolic pressure gradient (DPG [i.e., the difference between the diastolic pressure of the pulmonary artery and the pulmonary capillary wedge pressure]). This parameter helps reclassify those patients with PH and pulmonary capillary wedge pressure >15mmHg into 2 groups: isolated postcapillary PH, if the DPG is <7mmHg, and combined PH (precapillary and postcapillary), if the DPG is ≥7mmHg.<a class="elsevierStyleCrossRef" href="#bib0240">3</a> The latter group has greater vascular remodeling and mortality and replaces the previously named “disproportionate PH”.<a class="elsevierStyleCrossRef" href="#bib0255">6</a>Another important aspect incorporated into the guidelines is the identification of a risk group, characterized by patients who have ab mPAP between 21 and 24mmHg (normal value ≤20mmHg) and predisposing factors for developing PAH (connective tissue diseases, especially scleroderma, and first-degree relatives with hereditary or familial PAH). These cases should be closely monitored so that the onset of HAP can be detected early on.<a class="elsevierStyleCrossRefs" href="#bib0260">7,8</a>Lastly, the guidelines recommend a vascular reactivity test to select patients who can benefit from treatment with calcium antagonists but only in patients with idiopathic PAH. In the other patients, this test should not be performed routinely, because patients who “respond” are extremely rare, and the results can be unreliable.<a class="elsevierStyleCrossRef" href="#bib0270">9</a>New classification: what has changed?The classification into 5 groups (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) remains with few changes in terms of groups 2 and 3. A new term has been suggested for group 4: chronic thromboembolic PH and other pulmonary artery obstructions. For group 5 (unclear multifactorial mechanisms), the most relevant issue is the inclusion of an unusual hemodynamic condition, segmental PH, which occurs in patients with congenital heart disease (e.g., tricuspid or pulmonary atresia), in which only a specific area of the lung irrigated by aortopulmonary collateral vessels is affected. This group also includes PH secondary to chronic hemolytic anemia (previously belonging to group 1),<a class="elsevierStyleCrossRef" href="#bib0230">1</a> especially represented by sickle cell anemia, because the histological changes typical of vasculopathy (plexiform lesions) and the hemodynamic characteristics that define PAH have not been detected.<a class="elsevierStyleCrossRefs" href="#bib0275">10–12</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Group 1 can be associated with numerous diseases (such as human immunodeficiency virus infection, portal hypertension secondary to liver disease, connective tissue diseases, schistosomiasis and congenital heart disease) and hereditary/familial or idiopathic forms. Although there have not been significant advances in this group's classification, a number of developments have been incorporated:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020">(A)New mutations associated with the development of hereditary PAH have been found, specifically… (1) the mutation of caveolin-1 (CAV1), a membrane protein abundantly present in endothelial lung cells; (2) the mutation of KCNK3, a protein member-3 of the superfamily of potassium channels; and (3) the mutation of Smad 9 (mothers against decapentaplegic 9), a protein which belongs to the superfamily of transforming growth factor β (TGF-β). Even then, approximately 80% of patients with PAH have a BMPR2 (bone morphogenetic protein receptor 2) mutation, which also is part of the TGF-β superfamily.</li><li class="elsevierStyleListItem" id="lsti0025">(B)New drugs have been identified as potential causes of PAH. These findings are conclusive for benfluorex, a derivative of fenfluramine used as a hypoglycemic agent, and has already been withdrawn from European markets. There are also unequivocal data linking the use of serotonin reuptake inhibitors during pregnancy and the development of persistent PH in newborns. Other potential associations include the use of dasatinib (tyrosine kinase inhibitor used for treating chronic myeloproliferative syndromes), amphetamine mimetics (methylphenidate, phentermine, ropinirole and mazindol) and a possible relationship with interferon α and β, due to the fact that they induce the release of endothelin 1 in the pulmonary endothelial cells.</li><li class="elsevierStyleListItem" id="lsti0030">(C)Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, as well as persistent PH of the newborn, are now subgroups of group 1 (1′ and 1″, respectively).</li></ul>EpidemiologyThe PH of group 2 is considered the most common (present in up to 60–70% of patients with left ventricular dysfunction) and is, generally, mild to moderate. Within group 1, the disease most frequently associated with PAH globally is schistosomiasis, although it is not prevalent in the western world.<a class="elsevierStyleCrossRef" href="#bib0240">3</a>In Europe, the prevalence of PAH is estimated between 15 and 60 cases per million inhabitants, and the incidence rate is 5–10 cases per million individuals/year. Fifty percent of cases are hereditary, idiopathic or secondary to drugs. Among the diseases that predispose patients to the development of PAH, connective tissue diseases are the most common.<a class="elsevierStyleCrossRef" href="#bib0290">13</a> The prevalence of PH and PAH in Spain is estimated at 19.2 and 16 cases per million inhabitants, respectively. In the PAH group, the prevalence rates for idiopathic PAH, associated with congenital heart disease, connective tissue diseases and toxic oil syndrome are 5, 6, 3, 2.5 and 0.5 cases per million inhabitants, respectively. Additionally, the incidence rate for PAH appears to be somewhat lower than the European mean, the latter of which is 3.7 cases per million inhabitants/year.<a class="elsevierStyleCrossRef" href="#bib0295">14</a>The large national registries, such as the United States REVEAL registry and the French registry, have enabled data collection on the survival of these patients observing that the prognosis worsens when there is reduced cardiac output (i.e., a cardiac index <2.8L/min/m2).<a class="elsevierStyleCrossRef" href="#bib0300">15</a> The Spanish registry showed that survival at 1, 3 and 5 years for patients with PAH was 87%, 75% and 65%, respectively. This registry also observed that being male and an increase in right atrial pressure conferred an ominous prognosis.<a class="elsevierStyleCrossRef" href="#bib0295">14</a> Regardless of the study population, the leading cause of PAH-related death (50% of cases) is secondary right-sided heart failure.<a class="elsevierStyleCrossRef" href="#bib0305">16</a>Lastly, if a subanalysis is performed of the various PAH-related diseases, there is a notable poor prognosis associated with scleroderma, which represents 61% of cases of PAH related to connective tissue diseases in Spain.<a class="elsevierStyleCrossRef" href="#bib0295">14</a> Survival at 5 years for these patients is 8-fold lower than that for patients with scleroderma without PAH.<a class="elsevierStyleCrossRef" href="#bib0310">17</a>Pathophysiology: beyond the vesselIn recent years, the pathogenesis of PAH has been recognized as entailing complex interactions. Dysregulation between the innate and acquired immune system produces an autoimmune response that, through various soluble proinflammatory molecules, acts on the lung vascular wall,<a class="elsevierStyleCrossRef" href="#bib0315">18</a> resulting in the classically known changes of endothelial dysfunction, vasoconstriction, proliferation with endothelial remodeling and in situ thrombosis. These conditions ultimately produce progressive narrowing of the pulmonary vessels, which increases vascular resistance and therefore PAP.<a class="elsevierStyleCrossRef" href="#bib0320">19</a>The paradigm of this immunologic disorder consists of patients with scleroderma-associated PAH. Studies have shown that these patients frequently have anti-angiotensin type-1 receptor (anti-AT1R) antibodies and anti-endothelin type-A receptor (anti-ETAR) antibodies, which are also useful as prognostic markers.<a class="elsevierStyleCrossRef" href="#bib0325">20</a> However, we still do not know whether they are the cause or effect of PAH, of the pathogenic effects of hypoxia or of the effect of certain genetic determinants as potential triggers of this immune dysregulation.The immunopathology studies, which traditionally have focused on pulmonary artery smooth muscle, currently delve more into the role of pulmonary endothelial cells and fibroblasts, from which the metabolic theory of PAH emerges. This theory suggests that the cellular phenotype of PAH (mitochondrial hyperpolarization, reduction in mitochondrial reactive oxygen species, increase in intracytoplasmic calcium and histone acetylation suppression) could be due to mitochondrial oxidative phosphorylation inhibition, specifically of glucose oxidation. This inhibition results in a proinflammatory and antiapoptotic condition, which promotes cell proliferation in the pulmonary arteries. There is evidence (in rodent models) that these disorders could be the cause of PAH, which opens a new way of understanding the disease and the possibility for new therapeutic pathways.<a class="elsevierStyleCrossRef" href="#bib0330">21</a>DiagnosisThe clinical manifestations results from the right ventricular dysfunction. Exertional dyspnea is the earliest manifestation (85% of patients). In terms of additional examinations, the electrocardiogram (ECG) usually shows an axis deviation toward the right (>90°) and signs of atrial and right ventricular growth (p “pulmonale”, R ≥7mm in V1, R/S ≥1 in V1) in advanced stages. However, the ECG lacks sufficient sensitivity (55%) and specificity (70%) as a screening technique.<a class="elsevierStyleCrossRef" href="#bib0335">22</a> The chest radiography results are usually abnormal in more than 90% of patients at the time of diagnosis. An increase can be observed in the size of the pulmonary arteries (right interlobar pulmonary artery >16mm), narrowing of the peripheral vasculature and cardiomegaly at the expense of the right chambers.EchocardiogramECG helps measure systolic PAP, which depends on the presence of tricuspid regurgitation. In general, systolic PAP values >40mmHg are considered the cutoff for indicating right cardiac catheterization. The latest European guidelines recommend assigning a PAH probability level (low, medium or high) based on the echocardiographic findings (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). With these data, only those patients who have risk factors or diseases associated with PAH and a medium to high echocardiographic probability should undergo additional tests, including right cardiac catheterization.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The most useful feature of the echocardiogram lies in its ability to rule out signs of left-sided heart disease (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>) and to assess poor prognostic markers of right ventricular systolic function,<a class="elsevierStyleCrossRefs" href="#bib0340">23–25</a> such as pericardial effusion, a right atrial area >18cm2, an eccentricity index >1.1 and a reduction in tricuspid annular plane systolic excursion.<a class="elsevierStyleCrossRef" href="#bib0355">26</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Pulmonary function tests and 6-minute walking testSpirometry helps rule out the presence of underlying bronchopulmonary diseases. Moreover, a low reading on the diffusing capacity of the lungs for carbon monoxide test (<45% of the reference value) entails a poor outcome.The 6-minute walking test (6MWT) is the most standardized test for measuring the functional capacity and, until a few years ago, was the main variable for assessing the treatment response in clinical trials. Those patients with PAH who walked more than 330m in this test and those who had a maximal oxygen consumption at maximum effort of more than 15mL/kg/min in a stress test had greater survival. In contrast, a reduction of >10% in terms of the baseline oxygen saturation during the 6MWT is an indicator of severity.<a class="elsevierStyleCrossRefs" href="#bib0360">27,28</a>Ventilation/perfusion lung scintigraphyThis test should be performed in all patients with PH to rule out the forms secondary to chronic thromboembolic pulmonary hypertension. The test has higher sensitivity than computed tomography pulmonary angiography (CT angiography). Its diagnosis allows for the possibility of functional recovery and even healing through pulmonary endarterectomy.<a class="elsevierStyleCrossRef" href="#bib0370">29</a>CT angiography and high-resolution CTIn addition to the typical structural signs of PH (a diameter of the main pulmonary artery in the bifurcation >29mm and a pulmonary artery to aorta index >1), this is a complementary test to ventilated-perfusion scintigraphy for diagnosing forms secondary to chronic thromboembolic disease, especially for the assessment prior to pulmonary endarterectomy. CT angiography can be useful in assessing vasculitis and pulmonary arteriovenous malformations. Both high-resolution CT and CT angiography can provide information on the parenchyma's condition and are useful when suspecting veno-occlusive disease.<a class="elsevierStyleCrossRef" href="#bib0240">3</a>Cardiac magnetic resonance imagingThis test is the best tool for assessing right ventricular structure and function. It helps obtain information on the ejection volume, cardiac output, bulging of the interventricular septum and the RV mass ratio. A number of these findings, such as an end-diastolic volume of the right ventricle >88mL/m2, indicate a poor prognosis. Magnetic resonance angiography also helps assess pulmonary circulation parameters and the dilation and mean flow velocity of the pulmonary artery and the pulmonary vascular resistance.<a class="elsevierStyleCrossRef" href="#bib0375">30</a> In addition to the prognostic value, cardiac MRI enables a more reliable follow-up than with echocardiogram, which, in considerable measure, is observer-dependent.BiomarkersThe most useful markers are natriuretic peptides (brain natriuretic peptide [BNP] and N-terminal brain natriuretic propeptide [NT-proBNP]). Values higher than 150pg/mL of BNP or higher than 1800pg/mL of NT-proBNP are predictors of severity and are closely associated with right ventricular dysfunction. Their outpatient monitoring can be useful for assessing the treatment response.TreatmentThe European guidelines<a class="elsevierStyleCrossRef" href="#bib0240">3</a> recommend stratifying patients with PAH into 3 risk groups of disease progression. The objective is to reach a state of low risk of progression (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>) and improve the patients’ quality of life.<a class="elsevierStyleCrossRefs" href="#bib0240">3,26,31,32</a> Comprehensive patient treatment requires a complex and multidisciplinary strategy, which includes 3 basic aspects:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035">(1)General measures.</li><li class="elsevierStyleListItem" id="lsti0040">(2)Specific drug therapy of the PAH.</li><li class="elsevierStyleListItem" id="lsti0045">(3)Surgical treatment.</li></ul><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>General measuresDiuretics need to be employed at appropriate dosages to maintain euvolemia, along with oxygen therapy to correct hypoxemia (SpO2 goal ≥90%). Digoxin may also be employed, especially in those patients with right-sided heart failure and low output and those with atrial arrhythmia.<a class="elsevierStyleCrossRefs" href="#bib0240">3,26,31,32</a> The role of anticoagulation is uncertain, except in those patients with idiopathic PAH.<a class="elsevierStyleCrossRef" href="#bib0390">33</a>Other support measures include psychosocial support, prenatal guidance and avoiding strenuous or isometric exercise because these can precipitate syncope. A restricted salt diet is recommended, as is being up to date on vaccinations, of which the influenza and pneumococcal vaccinations are especially important.<a class="elsevierStyleCrossRef" href="#bib0385">32</a>Specific therapyThere are 3 major drug groups for treating PAH, each of which has a specific therapeutic target (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050">(1)Prostaglandin analogsProstacyclin (prostaglandin I2) causes pulmonary vasodilation through the synthesis of cyclic adenosine monophosphate. In the 1990s, the first clinical trials with a prostacyclin analog, epoprostenol, showed improvement in symptoms, exercise capacity, quality of life and hemodynamic parameters, as well as a reduced mortality, in a period of only 12 weeks. Epoprostenol was the first drug authorized for the treatment of PAH and is still considered the most effective. However, its short half-life, instability at room temperature, high cost and intravenous administration (IV) continue to limit its use. The EPITOME-2 study recently showed the efficacy and tolerance of a new formulation with excipients of arginine and sucrose (epoprostenol AS), instead of the excipients of glycine and mannitol (epoprostenol GM) in the standard formulation.<a class="elsevierStyleCrossRef" href="#bib0395">34</a> This new formulation gives it stability at room temperature of up to 72h, compared with the 12h of the standard formulation, which translates into greater convenience for the patient who has to reconstitute and load the epoprostenol solution.There are other currently available prostanoids: treprostinil (subcutaneous perfusion or IV, inhaled or oral) and iloprost (inhaled). The effects of these drugs as a whole are dose-dependent, and their use is normally limited to functional classes III–IV.</li><li class="elsevierStyleListItem" id="lsti0055">(2)Endothelin receptor antagonists (ERA)High levels of endothelin-1 cause vasoconstriction and endothelial proliferation. ERAs counteract this effect by binding to the endothelin receptors (receptors A and B) and are administered orally. Bosentan showed its efficacy by improving the distance traveled in the 6MWT and decreasing clinical worsening in 16 weeks.<a class="elsevierStyleCrossRef" href="#bib0400">35</a> Ambrisentan, a selective ERA (endothelin A receptor), and macitentan, a nonselective ERA, have a better pharmacokinetic profile, which allows for their administration in a single dose. The Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcomes compared macitentan against a placebo and showed a reduction in disease progression, including death, and clinical deterioration.<a class="elsevierStyleCrossRef" href="#bib0405">36</a> These benefits were observed both in patients who had not undergone treatment and those who had already undergone specific therapy for PAH.</li><li class="elsevierStyleListItem" id="lsti0060">(3)Phosphodiesterase-5 inhibitors (PDE5i) and soluble guanylate cyclase stimulantsAlthough they are 2 groups of drugs with different targets, both act on the nitric oxide pathway. Nitric oxide is a potent vasodilator and induces an increase in cyclic guanosine monophosphate and degrades by the action of PDE5. In PAH, there is reduced expression of nitric oxide synthase. The two PDE5i approved for treating PAH, sildenafil and tadalafil, increase nitric oxide levels preventing their degradation by PDE5.</li></ul><elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Riociguat, which stimulates soluble guanylate cyclase, directly increases cyclic guanosine monophosphate levels independently of nitric oxide, has shown a benefit in terms of exercise capacity, distance traveled in the 6MWT, reduction in pulmonary vascular resistances and delayed clinical worsening.<a class="elsevierStyleCrossRef" href="#bib0410">37</a> This drug is also the only one approved for treating PH associated with chronic thromboembolism.<a class="elsevierStyleCrossRef" href="#bib0415">38</a> The concomitant use of PDE5i and riociguat is contraindicated due to the risk of hypotension.Combined therapySequential therapy with a single drug has been employed in clinical practice.<a class="elsevierStyleCrossRef" href="#bib0420">39</a> A meta-analysis that included 6 clinical trials showed that combined therapy decreased the risk of clinical worsening by 52%, significantly increased (22m) the distance traveled in the 6MWT and improved the hemodynamic parameters.<a class="elsevierStyleCrossRef" href="#bib0425">40</a> These changes were achieved without increasing the risk of adverse events when compared with the control group but had no effect on overall mortality.The Bosentan Randomized Trial of Endothelin Antagonist Therapy-2 initially failed to demonstrate an improvement when using combined therapy with epoprostenol and bosentan, compared with epoprostenol in monotherapy.<a class="elsevierStyleCrossRef" href="#bib0430">41</a> More recently, the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension study, which compared combined therapy with ambrisentan and tadalafil against monotherapy with ambrisentan or tadalafil in patients with PAH of WHO functional class II or III, showed a 50% reduction in the primary objective (the sum of death, hospitalization, PAH progression or unsatisfactory clinical condition) in the first group.<a class="elsevierStyleCrossRef" href="#bib0435">42</a> The study also showed an improved capacity for exercise, improved NT-proBNP levels and improved clinical stage. While the international guidelines for PAH management recommend the use of sequential therapy, the latest European guidelines advocate initial combined therapy in WHO functional class IV. In functional classes II and III, both monotherapy and combined therapy are reasonable options. For combined therapy, the guidelines recommend the combination of tadalafil and ambrisentan.<a class="elsevierStyleCrossRef" href="#bib0240">3</a>Surgical treatmentIn the 1980s, transplantation was the only treatment available for PAH. Currently, this procedure is reserved for patients who, despite undergoing optimal medical treatment, show disease progression. The technique achieves a survival rate at 5 years of 50–75%.<a class="elsevierStyleCrossRef" href="#bib0440">43</a> The main indication for including a patient on a transplantation list is the presence of refractory symptoms (WHO FC-III–IV) despite combined triple therapy.<a class="elsevierStyleCrossRefs" href="#bib0240">3,31</a>Additionally, other techniques have been successful as a bridge to transplantation or as palliative treatment for those patients who are not candidates for transplantation. These techniques include balloon atrial septostomy and pulmonary artery denervation. Balloon atrial septostomy acts by mechanically decompressing the right chambers through the creation of an interatrial opening, thereby allowing for a right–left shunt.<a class="elsevierStyleCrossRefs" href="#bib0230">1,32,44</a> This translates into improved right cardiac output and oxygen transport, reduced right atrial pressure and lower sympathetic hyperactivity, especially in patients with WHO FC-IV.<a class="elsevierStyleCrossRef" href="#bib0450">45</a> However, careful preoperative selection should be performed to reduce perioperative mortality. Balloon atrial septostomy should be avoided in terminal patients, such as those with a right atrial pressure ≥20mmHg or an oxygen saturation ≤85% in environmental air. In regards to pulmonary artery denervation, a study that included 23 patients in a single center reported significant improvement in the hemodynamic parameters and the distance traveled in the 6MWT after this procedure.Conflict of interestThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres750237" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec752992" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres750236" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec752991" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Definitions" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "New classification: what has changed?" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Epidemiology" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Pathophysiology: beyond the vessel" ] ] ] 8 => array:3 [ "identificador" => "sec0030" "titulo" => "Diagnosis" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Echocardiogram" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Pulmonary function tests and 6-minute walking test" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Ventilation/perfusion lung scintigraphy" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "CT angiography and high-resolution CT" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Cardiac magnetic resonance imaging" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Biomarkers" ] ] ] 9 => array:3 [ "identificador" => "sec0065" "titulo" => "Treatment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "General measures" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Specific therapy" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Combined therapy" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Surgical treatment" ] ] ] 10 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec752992" "palabras" => array:6 [ 0 => "Pulmonary hypertension" 1 => "Pulmonary arterial hypertension" 2 => "Review" 3 => "Endothelin receptor antagonist" 4 => "Phosphodiesterase type 5 inhibitors" 5 => "Prostacyclin analogs" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec752991" "palabras" => array:6 [ 0 => "Hipertensión pulmonar" 1 => "Hipertensión arterial pulmonar" 2 => "Revisión" 3 => "Antagonista del receptor de endotelina" 4 => "Inhibidores de la fosfodiesterasa tipo 5" 5 => "Análagos de prostaciclina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Pulmonary arterial hypertension is a rare and progressive disease that mainly affects the pulmonary arterioles (precapillary), regardless of the triggering etiology. The prevalence of pulmonary hypertension and pulmonary arterial hypertension in Spain is estimated at 19.2 and 16 cases per million inhabitants, respectively. The diagnosis of pulmonary arterial hypertension is based on hemodynamic criteria (mean pulmonary artery pressure ≥25mmHg, pulmonary capillary wedge pressure ≤15mmHg and pulmonary vascular resistance >3 Wood units) and therefore requires the implementation of right cardiac catheterisation. Sequential therapy with a single drug has been used in clinical practice. However, recent European guidelines recommend combined initial therapy in some situations. This review conducts a critical update of our knowledge of this disease according to the latest guidelines and recommendations." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La hipertensión arterial pulmonar es una enfermedad rara y progresiva que afecta principalmente a las arteriolas pulmonares (precapilar), independientemente de la etiología desencadenante. En España se estima que la prevalencia de hipertensión pulmonar y de hipertensión arterial pulmonar es de 19,2 y 16 casos por millón de habitantes, respectivamente. El diagnóstico de hipertensión arterial pulmonar se basa en criterios hemodinámicos (presión media de la arteria pulmonar ≥25mmHg, presión de enclavamiento capilar pulmonar ≤15mmHg, y resistencia vascular pulmonar >3 unidades Wood) y por tanto requiere la realización de un cateterismo cardiaco derecho. En la práctica clínica se ha utilizado la terapia secuencial con un solo fármaco. Sin embargo, las recientes guías europeas recomiendan la terapia combinada de inicio en algunas situaciones. En esta revisión se realiza una actualización crítica de los conocimientos sobre esta enfermedad de acuerdo a las últimas guías y recomendaciones." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Chew CRM, Batres SA, Blanco JJR. Actualización en hipertensión arterial pulmonar. Rev Clin Esp. 2016;216:436–444." ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; HIV, human immunodeficiency virus; CTED, chronic thromboembolic disease; CKD, chronic kidney disease; EIF2AK4, eukaryotic translation initiation factor 2-alpha kinase 4.Modified from Galiè et al.<a class="elsevierStyleCrossRef" href="#bib0240">3</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group no. \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Associated diseases \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1. PAH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.1 Idiopathic 1.2 Hereditary (BMPR2 mutation or other) 1.3 Drugs and toxins 1.4 Associated with: 1.4.1 Connective tissue diseases 1.4.2 HIV 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1′. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1′.1 Idiopathic 1′.2 Hereditary (EIF2AK4 mutation or other) 1′.3 Drugs, toxins and radiation-induced 1′.4 Associated with connective tissue diseases or HIV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1′′. Persistent PH of the newborn \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2. PH secondary to left-sided heart disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular heart disease 2.4 Inflow/outlet tract obstruction 2.5 Pulmonary vein stenosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3. Secondary PH in pulmonary disease and/or hypoxia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.1 Chronic obstructive pulmonary disease 3.2 Diffuse interstitial lung disease 3.3 Mixed lung disease (e.g., restrictive and obstructive) 3.4 Sleep-related respiratory disorders 3.5 Alveolar hypoventilation syndromes 3.6 Long-term high altitude exposure 3.7 Lung development disorders \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4. PH secondary to CTED or pulmonary artery obstruction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.1 CTED 4.2 Other causes of obstruction: intravascular tumors such as angiosarcoma, arteritis, hydatidosis, and congenital pulmonary artery stenosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5. PH of multifactorial or undetermined mechanism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.1 Hematologic disorders: chronic hemolytic anemia, splenectomy, myeloproliferative syndromes 5.2 Systemic disorders: sarcoidosis, lymphangioleiomyomatosis, pulmonary histiocytosis 5.3 Metabolic disorders: Gaucher's disease, glycogenosis, thyroid diseases 5.4 Others: CKD, segmental PH \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1239634.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification of pulmonary hypertension." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Peak velocity of tricuspid regurgitation (m/s) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Other signs of pulmonary hypertension<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Degree of ultrasound probability \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">≤2.8 or not measurable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">≤2.8 or not measurable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Intermediate</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2.9–3.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2.9–3.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">High</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">>3.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not required \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1239637.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Ratio of the right and left ventricle diameters >1; flattening of the interventricular septum (left ventricle eccentricity index >1.1); diameter of the pulmonary artery >25mm; protodiastolic velocity of pulmonary regurgitation >2.2cm/s; Doppler acceleration time of the right ventricular outflow tract <105ms or midsystolic notch; right atrium area >18cm2; inferior vena cava diameter >21mm with reduced inspiratory collapse (<20% with deep breath or <50% with superficial breath). Modified from Galiè et al.<a class="elsevierStyleCrossRef" href="#bib0240">3</a>" ] ] ] "descripcion" => array:1 [ "en" => "Echocardiographic probability of pulmonary hypertension in symptomatic patients with suspected disease." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: PAH, pulmonary arterial hypertension; PVH, pulmonary venous hypertension; RV, right ventricle; LA, left atrium; E/A ratio, ratio between the velocity of the rapid and early filling phase (early) and the velocity of the late atrial contraction phase in the mitral valve measured by Doppler flow; E/e′ lateral, ratio of the early mitral filling velocity and the mitral protodiastolic tissue velocity; PCWP, pulmonary capillary wedge pressure; PADP, pulmonary artery diastolic pressure.Modified from Galiè et al.<a class="elsevierStyleCrossRef" href="#bib0240">3</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PAH \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PVH \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Echocardiogram</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Size of the RV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Can be increasing \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Size of the LA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RA/LA ratio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal (LA>RA) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Interventricular septum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bulges from right to left \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bulges from left to right \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Systolic deceleration of the RV outflow tract \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Common \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rare \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">E/A ratio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lateral e′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lateral E/e′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Hemodynamics</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aortic pressure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal or low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal or high \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PCWP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≤15mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>5mmHg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PADP–PCWP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>7mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><5mmHg \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1239638.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Difference between arterial and pulmonary venous hypertension." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Abbreviations: 6MWT, 6-minute walking test; BNP, brain natriuretic peptide; CI, cardiac index; MRI, magnetic resonance imaging; NT-proBNP, amino-terminal fraction of the brain natriuretic propeptide; RAA, right atrial area; RAP, right atrial pressure; SvO2, venous oxygen saturation; VO2, oxygen consumption; VE/VCO2, ventilatory equivalent for carbon dioxide; FC-WHO, functional class of the World Health Organization." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Prognostic factor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Low risk (<5%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intermediate risk (5–10%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">High risk (>10%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clinical signs of right heart failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Absent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Present \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Symptom progression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Slow \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fast \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Syncope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Occasional \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Frequent \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FC-WHO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I, II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6MWT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>440m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">165–440m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><165m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cardiopulmonary exercise test \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peak VO2 >15mL/min/kg (>65%<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a>) VE/VCO2<36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peak VO2 11–15mL/min/kg (35–65%) VE/VCO2 36–44.99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Peak VO2 <11mL/min/kg (<35%) VE/VCO2 >45 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NT-proBNP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BNP<50ng/L NT-proBNP<300ng/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BNP 50–300ng/L NT-proBNP 300–1400ng/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BNP>300ng/L NT-proBNP>1400ng/mL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Echocardiogram or cardiac MRI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RAA<18cm2 No pericardial effusion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RAA 18–26cm2 Minimal pericardial effusion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RAA>26cm2 Pericardial effusion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hemodynamic parameters \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RAP<8mmHg CI>2.5L/min/m2 SvO2>65% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RAP 8–14mmHg CI 2–2.4L/min/m2 SvO2 60–65% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RAP>14mmHg CI<2.0L/min/m2 SvO2<60% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1239636.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "The percentage is related to the reference value for age and sex. Modified from Galiè et al.<a class="elsevierStyleCrossRef" href="#bib0240">3</a>" ] ] ] "descripcion" => array:1 [ "en" => "Risk stratification of patients with pulmonary arterial hypertension." ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: SC, subcutaneously; IV, intravenously; kg, kilogram; mg, milligram; ng, nanogram; μg, microgram; h, hour; min, minute." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Administration route \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse Effects \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Epoprostenol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous IV perfusion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–40ng/kg/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypotension, flushing, nausea/vomiting, diarrhea, headache, thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Treprostinil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous IV perfusion Continuous SC perfusion Inhaled Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.25–40ng/kg/min 6μg/inhalation 3–9 inhalations in 4 sessions/day 0.125–2.5mg c/12–8h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mandibular pain, pain at the injection site, flushing, nausea, vomiting, diarrhea, headache \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Iloprost \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhaled \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5–5μg/inhalation 3–9 inhalations in 4 sessions/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cough, syncope, trismus, flushing, nausea, vomiting, diarrhea, headache \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bosentan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.5mg every 12h in month 1; then 125mg every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatotoxicity, anemia, peripheral edema, angina \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ambrisentan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5–10mg every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hepatotoxicity, coryza, sinusitis, peripheral edema \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macitentan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10mg every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anemia, hypotension, peripheral edema, hepatotoxicity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sildenafil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20mg every 8h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypotension, amaurosis, hearing loss, priapism, vaso-occlusive crisis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tadalafil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40mg every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypotension, amaurosis, hearing loss, priapism \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Riociguat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–2.5mg every 8h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Headaches, gastritis, dizziness, nausea, vomiting, hypotension, anemia \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1239635.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Drugs for treating pulmonary arterial hypertension." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0230" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Updated clinical classification of pulmonary hypertension" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. 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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pulmonary hypertension &#40;HP&#41; is classified into 5 groups according to the histopathological findings and hemodynamic profiles&#44; which involve a common therapeutic strategy&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Pulmonary arterial hypertension &#40;PAH&#41;&#44; which corresponds to group 1 of the classification&#44; is a rare &#40;5 cases per million individuals&#41; and progressive disease of the pulmonary vasculature that mainly affects the pulmonary arterioles &#40;precapillary&#41;&#44; regardless of the triggering etiology&#46; Without treatment&#44; PAH has an ominous prognosis&#44; with a mean survival similar to that of patients with metastatic breast cancer &#40;i&#46;e&#46;&#44; stage III&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In recent years&#44; there have been significant therapeutic developments in HP&#44; which have been collected in very recently published European guidelines&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">3&#44;4</span></a> This article is a clinical update mainly on PAH&#44; and its objective is to provide an update on the knowledge and developments of the pathogenesis&#44; diagnosis and treatment of this disease&#44; from a practical perspective for clinicians&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Definitions</span><p id="par0020" class="elsevierStylePara elsevierViewall">The diagnosis of PAH is based on hemodynamic criteria and therefore requires the implementation of right cardiac catheterization&#46; The hemodynamic parameters that need to be present for the diagnosis are as follows&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Mean pulmonary artery pressure &#40;mPAP&#41; &#8805;25<span class="elsevierStyleHsp" style=""></span>mmHg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Pulmonary capillary wedge pressure &#40;PCWP&#41; &#8804;15<span class="elsevierStyleHsp" style=""></span>mmHg&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Pulmonary vascular resistance &#62;3 Wood units&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">5</span></a></p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">These measurements are performed at rest&#46; The exercise-induced increase in mPAP increases with age and lacks a universal cutoff that can be used for defining PAH according to the mPAP measured after physical effort&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The latest European guidelines also recommend the measurement of the diastolic pressure gradient &#40;DPG &#91;i&#46;e&#46;&#44; the difference between the diastolic pressure of the pulmonary artery and the pulmonary capillary wedge pressure&#93;&#41;&#46; This parameter helps reclassify those patients with PH and pulmonary capillary wedge pressure &#62;15<span class="elsevierStyleHsp" style=""></span>mmHg into 2 groups&#58; isolated postcapillary PH&#44; if the DPG is &#60;7<span class="elsevierStyleHsp" style=""></span>mmHg&#44; and combined PH &#40;precapillary and postcapillary&#41;&#44; if the DPG is &#8805;7<span class="elsevierStyleHsp" style=""></span>mmHg&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a> The latter group has greater vascular remodeling and mortality and replaces the previously named &#8220;disproportionate PH&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">6</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Another important aspect incorporated into the guidelines is the identification of a risk group&#44; characterized by patients who have ab mPAP between 21 and 24<span class="elsevierStyleHsp" style=""></span>mmHg &#40;normal value &#8804;20<span class="elsevierStyleHsp" style=""></span>mmHg&#41; and predisposing factors for developing PAH &#40;connective tissue diseases&#44; especially scleroderma&#44; and first-degree relatives with hereditary or familial PAH&#41;&#46; These cases should be closely monitored so that the onset of HAP can be detected early on&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Lastly&#44; the guidelines recommend a vascular reactivity test to select patients who can benefit from treatment with calcium antagonists but only in patients with idiopathic PAH&#46; In the other patients&#44; this test should not be performed routinely&#44; because patients who &#8220;respond&#8221; are extremely rare&#44; and the results can be unreliable&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">New classification&#58; what has changed&#63;</span><p id="par0060" class="elsevierStylePara elsevierViewall">The classification into 5 groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; remains with few changes in terms of groups 2 and 3&#46; A new term has been suggested for group 4&#58; chronic thromboembolic PH and other pulmonary artery obstructions&#46; For group 5 &#40;unclear multifactorial mechanisms&#41;&#44; the most relevant issue is the inclusion of an unusual hemodynamic condition&#44; segmental PH&#44; which occurs in patients with congenital heart disease &#40;e&#46;g&#46;&#44; tricuspid or pulmonary atresia&#41;&#44; in which only a specific area of the lung irrigated by aortopulmonary collateral vessels is affected&#46; This group also includes PH secondary to chronic hemolytic anemia &#40;previously belonging to group 1&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">1</span></a> especially represented by sickle cell anemia&#44; because the histological changes typical of vasculopathy &#40;plexiform lesions&#41; and the hemodynamic characteristics that define PAH have not been detected&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">10&#8211;12</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Group 1 can be associated with numerous diseases &#40;such as human immunodeficiency virus infection&#44; portal hypertension secondary to liver disease&#44; connective tissue diseases&#44; schistosomiasis and congenital heart disease&#41; and hereditary&#47;familial or idiopathic forms&#46; Although there have not been significant advances in this group&#39;s classification&#44; a number of developments have been incorporated&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#40;A&#41;</span><p id="par0070" class="elsevierStylePara elsevierViewall">New mutations associated with the development of hereditary PAH have been found&#44; specifically&#8230; &#40;1&#41; the mutation of caveolin-1 &#40;CAV1&#41;&#44; a membrane protein abundantly present in endothelial lung cells&#59; &#40;2&#41; the mutation of KCNK3&#44; a protein member-3 of the superfamily of potassium channels&#59; and &#40;3&#41; the mutation of Smad 9 &#40;mothers against decapentaplegic 9&#41;&#44; a protein which belongs to the superfamily of transforming growth factor &#946; &#40;TGF-&#946;&#41;&#46; Even then&#44; approximately 80&#37; of patients with PAH have a BMPR2 &#40;bone morphogenetic protein receptor 2&#41; mutation&#44; which also is part of the TGF-&#946; superfamily&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#40;B&#41;</span><p id="par0075" class="elsevierStylePara elsevierViewall">New drugs have been identified as potential causes of PAH&#46; These findings are conclusive for benfluorex&#44; a derivative of fenfluramine used as a hypoglycemic agent&#44; and has already been withdrawn from European markets&#46; There are also unequivocal data linking the use of serotonin reuptake inhibitors during pregnancy and the development of persistent PH in newborns&#46; Other potential associations include the use of dasatinib &#40;tyrosine kinase inhibitor used for treating chronic myeloproliferative syndromes&#41;&#44; amphetamine mimetics &#40;methylphenidate&#44; phentermine&#44; ropinirole and mazindol&#41; and a possible relationship with interferon &#945; and &#946;&#44; due to the fact that they induce the release of endothelin 1 in the pulmonary endothelial cells&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#40;C&#41;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis&#44; as well as persistent PH of the newborn&#44; are now subgroups of group 1 &#40;1&#8242; and 1&#8243;&#44; respectively&#41;&#46;</p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Epidemiology</span><p id="par0085" class="elsevierStylePara elsevierViewall">The PH of group 2 is considered the most common &#40;present in up to 60&#8211;70&#37; of patients with left ventricular dysfunction&#41; and is&#44; generally&#44; mild to moderate&#46; Within group 1&#44; the disease most frequently associated with PAH globally is schistosomiasis&#44; although it is not prevalent in the western world&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In Europe&#44; the prevalence of PAH is estimated between 15 and 60 cases per million inhabitants&#44; and the incidence rate is 5&#8211;10 cases per million individuals&#47;year&#46; Fifty percent of cases are hereditary&#44; idiopathic or secondary to drugs&#46; Among the diseases that predispose patients to the development of PAH&#44; connective tissue diseases are the most common&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">13</span></a> The prevalence of PH and PAH in Spain is estimated at 19&#46;2 and 16 cases per million inhabitants&#44; respectively&#46; In the PAH group&#44; the prevalence rates for idiopathic PAH&#44; associated with congenital heart disease&#44; connective tissue diseases and toxic oil syndrome are 5&#44; 6&#44; 3&#44; 2&#46;5 and 0&#46;5 cases per million inhabitants&#44; respectively&#46; Additionally&#44; the incidence rate for PAH appears to be somewhat lower than the European mean&#44; the latter of which is 3&#46;7 cases per million inhabitants&#47;year&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">14</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The large national registries&#44; such as the United States REVEAL registry and the French registry&#44; have enabled data collection on the survival of these patients observing that the prognosis worsens when there is reduced cardiac output &#40;i&#46;e&#46;&#44; a cardiac index &#60;2&#46;8<span class="elsevierStyleHsp" style=""></span>L&#47;min&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">15</span></a> The Spanish registry showed that survival at 1&#44; 3 and 5 years for patients with PAH was 87&#37;&#44; 75&#37; and 65&#37;&#44; respectively&#46; This registry also observed that being male and an increase in right atrial pressure conferred an ominous prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">14</span></a> Regardless of the study population&#44; the leading cause of PAH-related death &#40;50&#37; of cases&#41; is secondary right-sided heart failure&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">16</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Lastly&#44; if a subanalysis is performed of the various PAH-related diseases&#44; there is a notable poor prognosis associated with scleroderma&#44; which represents 61&#37; of cases of PAH related to connective tissue diseases in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">14</span></a> Survival at 5 years for these patients is 8-fold lower than that for patients with scleroderma without PAH&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">17</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Pathophysiology&#58; beyond the vessel</span><p id="par0105" class="elsevierStylePara elsevierViewall">In recent years&#44; the pathogenesis of PAH has been recognized as entailing complex interactions&#46; Dysregulation between the innate and acquired immune system produces an autoimmune response that&#44; through various soluble proinflammatory molecules&#44; acts on the lung vascular wall&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">18</span></a> resulting in the classically known changes of endothelial dysfunction&#44; vasoconstriction&#44; proliferation with endothelial remodeling and in situ thrombosis&#46; These conditions ultimately produce progressive narrowing of the pulmonary vessels&#44; which increases vascular resistance and therefore PAP&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">19</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The paradigm of this immunologic disorder consists of patients with scleroderma-associated PAH&#46; Studies have shown that these patients frequently have anti-angiotensin type-1 receptor &#40;anti-AT1R&#41; antibodies and anti-endothelin type-A receptor &#40;anti-ET<span class="elsevierStyleInf">A</span>R&#41; antibodies&#44; which are also useful as prognostic markers&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">20</span></a> However&#44; we still do not know whether they are the cause or effect of PAH&#44; of the pathogenic effects of hypoxia or of the effect of certain genetic determinants as potential triggers of this immune dysregulation&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The immunopathology studies&#44; which traditionally have focused on pulmonary artery smooth muscle&#44; currently delve more into the role of pulmonary endothelial cells and fibroblasts&#44; from which the metabolic theory of PAH emerges&#46; This theory suggests that the cellular phenotype of PAH &#40;mitochondrial hyperpolarization&#44; reduction in mitochondrial reactive oxygen species&#44; increase in intracytoplasmic calcium and histone acetylation suppression&#41; could be due to mitochondrial oxidative phosphorylation inhibition&#44; specifically of glucose oxidation&#46; This inhibition results in a proinflammatory and antiapoptotic condition&#44; which promotes cell proliferation in the pulmonary arteries&#46; There is evidence &#40;in rodent models&#41; that these disorders could be the cause of PAH&#44; which opens a new way of understanding the disease and the possibility for new therapeutic pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">21</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Diagnosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">The clinical manifestations results from the right ventricular dysfunction&#46; Exertional dyspnea is the earliest manifestation &#40;85&#37; of patients&#41;&#46; In terms of additional examinations&#44; the electrocardiogram &#40;ECG&#41; usually shows an axis deviation toward the right &#40;&#62;90&#176;&#41; and signs of atrial and right ventricular growth &#40;p &#8220;pulmonale&#8221;&#44; R &#8805;7<span class="elsevierStyleHsp" style=""></span>mm in V1&#44; R&#47;S &#8805;1 in V1&#41; in advanced stages&#46; However&#44; the ECG lacks sufficient sensitivity &#40;55&#37;&#41; and specificity &#40;70&#37;&#41; as a screening technique&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">22</span></a> The chest radiography results are usually abnormal in more than 90&#37; of patients at the time of diagnosis&#46; An increase can be observed in the size of the pulmonary arteries &#40;right interlobar pulmonary artery &#62;16<span class="elsevierStyleHsp" style=""></span>mm&#41;&#44; narrowing of the peripheral vasculature and cardiomegaly at the expense of the right chambers&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Echocardiogram</span><p id="par0125" class="elsevierStylePara elsevierViewall">ECG helps measure systolic PAP&#44; which depends on the presence of tricuspid regurgitation&#46; In general&#44; systolic PAP values &#62;40<span class="elsevierStyleHsp" style=""></span>mmHg are considered the cutoff for indicating right cardiac catheterization&#46; The latest European guidelines recommend assigning a PAH probability level &#40;low&#44; medium or high&#41; based on the echocardiographic findings &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; With these data&#44; only those patients who have risk factors or diseases associated with PAH and a medium to high echocardiographic probability should undergo additional tests&#44; including right cardiac catheterization&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">The most useful feature of the echocardiogram lies in its ability to rule out signs of left-sided heart disease &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; and to assess poor prognostic markers of right ventricular systolic function&#44;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">23&#8211;25</span></a> such as pericardial effusion&#44; a right atrial area &#62;18<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span>&#44; an eccentricity index &#62;1&#46;1 and a reduction in tricuspid annular plane systolic excursion&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">26</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Pulmonary function tests and 6-minute walking test</span><p id="par0135" class="elsevierStylePara elsevierViewall">Spirometry helps rule out the presence of underlying bronchopulmonary diseases&#46; Moreover&#44; a low reading on the diffusing capacity of the lungs for carbon monoxide test &#40;&#60;45&#37; of the reference value&#41; entails a poor outcome&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The 6-minute walking test &#40;6MWT&#41; is the most standardized test for measuring the functional capacity and&#44; until a few years ago&#44; was the main variable for assessing the treatment response in clinical trials&#46; Those patients with PAH who walked more than 330<span class="elsevierStyleHsp" style=""></span>m in this test and those who had a maximal oxygen consumption at maximum effort of more than 15<span class="elsevierStyleHsp" style=""></span>mL&#47;kg&#47;min in a stress test had greater survival&#46; In contrast&#44; a reduction of &#62;10&#37; in terms of the baseline oxygen saturation during the 6MWT is an indicator of severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">27&#44;28</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Ventilation&#47;perfusion lung scintigraphy</span><p id="par0145" class="elsevierStylePara elsevierViewall">This test should be performed in all patients with PH to rule out the forms secondary to chronic thromboembolic pulmonary hypertension&#46; The test has higher sensitivity than computed tomography pulmonary angiography &#40;CT angiography&#41;&#46; Its diagnosis allows for the possibility of functional recovery and even healing through pulmonary endarterectomy&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">CT angiography and high-resolution CT</span><p id="par0150" class="elsevierStylePara elsevierViewall">In addition to the typical structural signs of PH &#40;a diameter of the main pulmonary artery in the bifurcation &#62;29<span class="elsevierStyleHsp" style=""></span>mm and a pulmonary artery to aorta index &#62;1&#41;&#44; this is a complementary test to ventilated-perfusion scintigraphy for diagnosing forms secondary to chronic thromboembolic disease&#44; especially for the assessment prior to pulmonary endarterectomy&#46; CT angiography can be useful in assessing vasculitis and pulmonary arteriovenous malformations&#46; Both high-resolution CT and CT angiography can provide information on the parenchyma&#39;s condition and are useful when suspecting veno-occlusive disease&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cardiac magnetic resonance imaging</span><p id="par0155" class="elsevierStylePara elsevierViewall">This test is the best tool for assessing right ventricular structure and function&#46; It helps obtain information on the ejection volume&#44; cardiac output&#44; bulging of the interventricular septum and the RV mass ratio&#46; A number of these findings&#44; such as an end-diastolic volume of the right ventricle &#62;88<span class="elsevierStyleHsp" style=""></span>mL&#47;m<span class="elsevierStyleSup">2</span>&#44; indicate a poor prognosis&#46; Magnetic resonance angiography also helps assess pulmonary circulation parameters and the dilation and mean flow velocity of the pulmonary artery and the pulmonary vascular resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">30</span></a> In addition to the prognostic value&#44; cardiac MRI enables a more reliable follow-up than with echocardiogram&#44; which&#44; in considerable measure&#44; is observer-dependent&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Biomarkers</span><p id="par0160" class="elsevierStylePara elsevierViewall">The most useful markers are natriuretic peptides &#40;brain natriuretic peptide &#91;BNP&#93; and N-terminal brain natriuretic propeptide &#91;NT-proBNP&#93;&#41;&#46; Values higher than 150<span class="elsevierStyleHsp" style=""></span>pg&#47;mL of BNP or higher than 1800<span class="elsevierStyleHsp" style=""></span>pg&#47;mL of NT-proBNP are predictors of severity and are closely associated with right ventricular dysfunction&#46; Their outpatient monitoring can be useful for assessing the treatment response&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment</span><p id="par0165" class="elsevierStylePara elsevierViewall">The European guidelines<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a> recommend stratifying patients with PAH into 3 risk groups of disease progression&#46; The objective is to reach a state of low risk of progression &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41; and improve the patients&#8217; quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">3&#44;26&#44;31&#44;32</span></a> Comprehensive patient treatment requires a complex and multidisciplinary strategy&#44; which includes 3 basic aspects&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#40;1&#41;</span><p id="par0170" class="elsevierStylePara elsevierViewall">General measures&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#40;2&#41;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Specific drug therapy of the PAH&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#40;3&#41;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Surgical treatment&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">General measures</span><p id="par0185" class="elsevierStylePara elsevierViewall">Diuretics need to be employed at appropriate dosages to maintain euvolemia&#44; along with oxygen therapy to correct hypoxemia &#40;SpO<span class="elsevierStyleInf">2</span> goal &#8805;90&#37;&#41;&#46; Digoxin may also be employed&#44; especially in those patients with right-sided heart failure and low output and those with atrial arrhythmia&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">3&#44;26&#44;31&#44;32</span></a> The role of anticoagulation is uncertain&#44; except in those patients with idiopathic PAH&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">33</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Other support measures include psychosocial support&#44; prenatal guidance and avoiding strenuous or isometric exercise because these can precipitate syncope&#46; A restricted salt diet is recommended&#44; as is being up to date on vaccinations&#44; of which the influenza and pneumococcal vaccinations are especially important&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Specific therapy</span><p id="par0195" class="elsevierStylePara elsevierViewall">There are 3 major drug groups for treating PAH&#44; each of which has a specific therapeutic target &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#40;1&#41;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Prostaglandin analogs</p><p id="par0205" class="elsevierStylePara elsevierViewall">Prostacyclin &#40;prostaglandin I<span class="elsevierStyleInf">2</span>&#41; causes pulmonary vasodilation through the synthesis of cyclic adenosine monophosphate&#46; In the 1990s&#44; the first clinical trials with a prostacyclin analog&#44; epoprostenol&#44; showed improvement in symptoms&#44; exercise capacity&#44; quality of life and hemodynamic parameters&#44; as well as a reduced mortality&#44; in a period of only 12 weeks&#46; Epoprostenol was the first drug authorized for the treatment of PAH and is still considered the most effective&#46; However&#44; its short half-life&#44; instability at room temperature&#44; high cost and intravenous administration &#40;IV&#41; continue to limit its use&#46; The EPITOME-2 study recently showed the efficacy and tolerance of a new formulation with excipients of arginine and sucrose &#40;epoprostenol AS&#41;&#44; instead of the excipients of glycine and mannitol &#40;epoprostenol GM&#41; in the standard formulation&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">34</span></a> This new formulation gives it stability at room temperature of up to 72<span class="elsevierStyleHsp" style=""></span>h&#44; compared with the 12<span class="elsevierStyleHsp" style=""></span>h of the standard formulation&#44; which translates into greater convenience for the patient who has to reconstitute and load the epoprostenol solution&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">There are other currently available prostanoids&#58; treprostinil &#40;subcutaneous perfusion or IV&#44; inhaled or oral&#41; and iloprost &#40;inhaled&#41;&#46; The effects of these drugs as a whole are dose-dependent&#44; and their use is normally limited to functional classes III&#8211;IV&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#40;2&#41;</span><p id="par0215" class="elsevierStylePara elsevierViewall">Endothelin receptor antagonists &#40;ERA&#41;</p><p id="par0220" class="elsevierStylePara elsevierViewall">High levels of endothelin-1 cause vasoconstriction and endothelial proliferation&#46; ERAs counteract this effect by binding to the endothelin receptors &#40;receptors A and B&#41; and are administered orally&#46; Bosentan showed its efficacy by improving the distance traveled in the 6MWT and decreasing clinical worsening in 16 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">35</span></a> Ambrisentan&#44; a selective ERA &#40;endothelin A receptor&#41;&#44; and macitentan&#44; a nonselective ERA&#44; have a better pharmacokinetic profile&#44; which allows for their administration in a single dose&#46; The Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcomes compared macitentan against a placebo and showed a reduction in disease progression&#44; including death&#44; and clinical deterioration&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">36</span></a> These benefits were observed both in patients who had not undergone treatment and those who had already undergone specific therapy for PAH&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#40;3&#41;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Phosphodiesterase-5 inhibitors &#40;PDE5i&#41; and soluble guanylate cyclase stimulants</p><p id="par0230" class="elsevierStylePara elsevierViewall">Although they are 2 groups of drugs with different targets&#44; both act on the nitric oxide pathway&#46; Nitric oxide is a potent vasodilator and induces an increase in cyclic guanosine monophosphate and degrades by the action of PDE5&#46; In PAH&#44; there is reduced expression of nitric oxide synthase&#46; The two PDE5i approved for treating PAH&#44; sildenafil and tadalafil&#44; increase nitric oxide levels preventing their degradation by PDE5&#46;</p></li></ul></p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0235" class="elsevierStylePara elsevierViewall">Riociguat&#44; which stimulates soluble guanylate cyclase&#44; directly increases cyclic guanosine monophosphate levels independently of nitric oxide&#44; has shown a benefit in terms of exercise capacity&#44; distance traveled in the 6MWT&#44; reduction in pulmonary vascular resistances and delayed clinical worsening&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">37</span></a> This drug is also the only one approved for treating PH associated with chronic thromboembolism&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">38</span></a> The concomitant use of PDE5i and riociguat is contraindicated due to the risk of hypotension&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Combined therapy</span><p id="par0240" class="elsevierStylePara elsevierViewall">Sequential therapy with a single drug has been employed in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">39</span></a> A meta-analysis that included 6 clinical trials showed that combined therapy decreased the risk of clinical worsening by 52&#37;&#44; significantly increased &#40;22<span class="elsevierStyleHsp" style=""></span>m&#41; the distance traveled in the 6MWT and improved the hemodynamic parameters&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">40</span></a> These changes were achieved without increasing the risk of adverse events when compared with the control group but had no effect on overall mortality&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The Bosentan Randomized Trial of Endothelin Antagonist Therapy-2 initially failed to demonstrate an improvement when using combined therapy with epoprostenol and bosentan&#44; compared with epoprostenol in monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">41</span></a> More recently&#44; the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension study&#44; which compared combined therapy with ambrisentan and tadalafil against monotherapy with ambrisentan or tadalafil in patients with PAH of WHO functional class II or III&#44; showed a 50&#37; reduction in the primary objective &#40;the sum of death&#44; hospitalization&#44; PAH progression or unsatisfactory clinical condition&#41; in the first group&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">42</span></a> The study also showed an improved capacity for exercise&#44; improved NT-proBNP levels and improved clinical stage&#46; While the international guidelines for PAH management recommend the use of sequential therapy&#44; the latest European guidelines advocate initial combined therapy in WHO functional class IV&#46; In functional classes II and III&#44; both monotherapy and combined therapy are reasonable options&#46; For combined therapy&#44; the guidelines recommend the combination of tadalafil and ambrisentan&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Surgical treatment</span><p id="par0250" class="elsevierStylePara elsevierViewall">In the 1980s&#44; transplantation was the only treatment available for PAH&#46; Currently&#44; this procedure is reserved for patients who&#44; despite undergoing optimal medical treatment&#44; show disease progression&#46; The technique achieves a survival rate at 5 years of 50&#8211;75&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">43</span></a> The main indication for including a patient on a transplantation list is the presence of refractory symptoms &#40;WHO FC-III&#8211;IV&#41; despite combined triple therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">3&#44;31</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Additionally&#44; other techniques have been successful as a bridge to transplantation or as palliative treatment for those patients who are not candidates for transplantation&#46; These techniques include balloon atrial septostomy and pulmonary artery denervation&#46; Balloon atrial septostomy acts by mechanically decompressing the right chambers through the creation of an interatrial opening&#44; thereby allowing for a right&#8211;left shunt&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">1&#44;32&#44;44</span></a> This translates into improved right cardiac output and oxygen transport&#44; reduced right atrial pressure and lower sympathetic hyperactivity&#44; especially in patients with WHO FC-IV&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">45</span></a> However&#44; careful preoperative selection should be performed to reduce perioperative mortality&#46; Balloon atrial septostomy should be avoided in terminal patients&#44; such as those with a right atrial pressure &#8805;20<span class="elsevierStyleHsp" style=""></span>mmHg or an oxygen saturation &#8804;85&#37; in environmental air&#46; In regards to pulmonary artery denervation&#44; a study that included 23 patients in a single center reported significant improvement in the hemodynamic parameters and the distance traveled in the 6MWT after this procedure&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0260" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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            0 => "Pulmonary hypertension"
            1 => "Pulmonary arterial hypertension"
            2 => "Review"
            3 => "Endothelin receptor antagonist"
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            0 => "Hipertensi&#243;n pulmonar"
            1 => "Hipertensi&#243;n arterial pulmonar"
            2 => "Revisi&#243;n"
            3 => "Antagonista del receptor de endotelina"
            4 => "Inhibidores de la fosfodiesterasa tipo 5"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pulmonary arterial hypertension is a rare and progressive disease that mainly affects the pulmonary arterioles &#40;precapillary&#41;&#44; regardless of the triggering etiology&#46; The prevalence of pulmonary hypertension and pulmonary arterial hypertension in Spain is estimated at 19&#46;2 and 16 cases per million inhabitants&#44; respectively&#46; The diagnosis of pulmonary arterial hypertension is based on hemodynamic criteria &#40;mean pulmonary artery pressure &#8805;25<span class="elsevierStyleHsp" style=""></span>mmHg&#44; pulmonary capillary wedge pressure &#8804;15<span class="elsevierStyleHsp" style=""></span>mmHg and pulmonary vascular resistance &#62;3 Wood units&#41; and therefore requires the implementation of right cardiac catheterisation&#46; Sequential therapy with a single drug has been used in clinical practice&#46; However&#44; recent European guidelines recommend combined initial therapy in some situations&#46; This review conducts a critical update of our knowledge of this disease according to the latest guidelines and recommendations&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La hipertensi&#243;n arterial pulmonar es una enfermedad rara y progresiva que afecta principalmente a las arteriolas pulmonares &#40;precapilar&#41;&#44; independientemente de la etiolog&#237;a desencadenante&#46; En Espa&#241;a se estima que la prevalencia de hipertensi&#243;n pulmonar y de hipertensi&#243;n arterial pulmonar es de 19&#44;2 y 16 casos por mill&#243;n de habitantes&#44; respectivamente&#46; El diagn&#243;stico de hipertensi&#243;n arterial pulmonar se basa en criterios hemodin&#225;micos &#40;presi&#243;n media de la arteria pulmonar &#8805;25<span class="elsevierStyleHsp" style=""></span>mmHg&#44; presi&#243;n de enclavamiento capilar pulmonar &#8804;15<span class="elsevierStyleHsp" style=""></span>mmHg&#44; y resistencia vascular pulmonar &#62;3 unidades Wood&#41; y por tanto requiere la realizaci&#243;n de un cateterismo cardiaco derecho&#46; En la pr&#225;ctica cl&#237;nica se ha utilizado la terapia secuencial con un solo f&#225;rmaco&#46; Sin embargo&#44; las recientes gu&#237;as europeas recomiendan la terapia combinada de inicio en algunas situaciones&#46; En esta revisi&#243;n se realiza una actualizaci&#243;n cr&#237;tica de los conocimientos sobre esta enfermedad de acuerdo a las &#250;ltimas gu&#237;as y recomendaciones&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; Chew CRM&#44; Batres SA&#44; Blanco JJR&#46; Actualizaci&#243;n en hipertensi&#243;n arterial pulmonar&#46; Rev Clin Esp&#46; 2016&#59;216&#58;436&#8211;444&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; PH&#44; pulmonary hypertension&#59; PAH&#44; pulmonary arterial hypertension&#59; HIV&#44; human immunodeficiency virus&#59; CTED&#44; chronic thromboembolic disease&#59; CKD&#44; chronic kidney disease&#59; EIF2AK4&#44; eukaryotic translation initiation factor 2-alpha kinase 4&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Modified from Gali&#232; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a></p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group no&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Associated diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&#46; PAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;1 Idiopathic<br>1&#46;2 Hereditary &#40;BMPR2 mutation or other&#41;<br>1&#46;3 Drugs and toxins<br>1&#46;4 Associated with&#58;<br><span class="elsevierStyleHsp" style=""></span>1&#46;4&#46;1 Connective tissue diseases<br><span class="elsevierStyleHsp" style=""></span>1&#46;4&#46;2 HIV<br><span class="elsevierStyleHsp" style=""></span>1&#46;4&#46;3 Portal hypertension<br><span class="elsevierStyleHsp" style=""></span>1&#46;4&#46;4 Congenital heart disease<br><span class="elsevierStyleHsp" style=""></span>1&#46;4&#46;5 Schistosomiasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&#8242;&#46; Pulmonary veno-occlusive disease and&#47;or pulmonary capillary hemangiomatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8242;&#46;1 Idiopathic<br>1&#8242;&#46;2 Hereditary &#40;EIF2AK4 mutation or other&#41;<br>1&#8242;&#46;3 Drugs&#44; toxins and radiation-induced<br>1&#8242;&#46;4 Associated with connective tissue diseases or HIV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&#8242;&#8242;&#46; Persistent PH of the newborn&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&#46; PH secondary to left-sided heart disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;1 Left ventricular systolic dysfunction<br>2&#46;2 Left ventricular diastolic dysfunction<br>2&#46;3 Valvular heart disease<br>2&#46;4 Inflow&#47;outlet tract obstruction<br>2&#46;5 Pulmonary vein stenosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&#46; Secondary PH in pulmonary disease and&#47;or hypoxia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;1 Chronic obstructive pulmonary disease<br>3&#46;2 Diffuse interstitial lung disease<br>3&#46;3 Mixed lung disease &#40;e&#46;g&#46;&#44; restrictive and obstructive&#41;<br>3&#46;4 Sleep-related respiratory disorders<br>3&#46;5 Alveolar hypoventilation syndromes<br>3&#46;6 Long-term high altitude exposure<br>3&#46;7 Lung development disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&#46; PH secondary to CTED or pulmonary artery obstruction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;1 CTED<br>4&#46;2 Other causes of obstruction&#58; intravascular tumors such as angiosarcoma&#44; arteritis&#44; hydatidosis&#44; and congenital pulmonary artery stenosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&#46; PH of multifactorial or undetermined mechanism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;1 Hematologic disorders&#58; chronic hemolytic anemia&#44; splenectomy&#44; myeloproliferative syndromes<br>5&#46;2 Systemic disorders&#58; sarcoidosis&#44; lymphangioleiomyomatosis&#44; pulmonary histiocytosis<br>5&#46;3 Metabolic disorders&#58; Gaucher&#39;s disease&#44; glycogenosis&#44; thyroid diseases<br>5&#46;4 Others&#58; CKD&#44; segmental PH&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Peak velocity of tricuspid regurgitation &#40;m&#47;s&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Other signs of pulmonary hypertension<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Degree of ultrasound probability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8804;2&#46;8 or not measurable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8804;2&#46;8 or not measurable&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&#46;9&#8211;3&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">High</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#62;3&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not required&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1239637.png"
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Ratio of the right and left ventricle diameters &#62;1&#59; flattening of the interventricular septum &#40;left ventricle eccentricity index &#62;1&#46;1&#41;&#59; diameter of the pulmonary artery &#62;25<span class="elsevierStyleHsp" style=""></span>mm&#59; protodiastolic velocity of pulmonary regurgitation &#62;2&#46;2<span class="elsevierStyleHsp" style=""></span>cm&#47;s&#59; Doppler acceleration time of the right ventricular outflow tract &#60;105<span class="elsevierStyleHsp" style=""></span>ms or midsystolic notch&#59; right atrium area &#62;18<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span>&#59; inferior vena cava diameter &#62;21<span class="elsevierStyleHsp" style=""></span>mm with reduced inspiratory collapse &#40;&#60;20&#37; with deep breath or &#60;50&#37; with superficial breath&#41;&#46;</p> <p class="elsevierStyleNotepara" id="npar0010">Modified from Gali&#232; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a></p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Echocardiographic probability of pulmonary hypertension in symptomatic patients with suspected disease&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; PAH&#44; pulmonary arterial hypertension&#59; PVH&#44; pulmonary venous hypertension&#59; RV&#44; right ventricle&#59; LA&#44; left atrium&#59; E&#47;A ratio&#44; ratio between the velocity of the rapid and early filling phase &#40;early&#41; and the velocity of the late atrial contraction phase in the mitral valve measured by Doppler flow&#59; E&#47;e&#8242; lateral&#44; ratio of the early mitral filling velocity and the mitral protodiastolic tissue velocity&#59; PCWP&#44; pulmonary capillary wedge pressure&#59; PADP&#44; pulmonary artery diastolic pressure&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Modified from Gali&#232; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a></p>"
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            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">PVH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Echocardiogram</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Size of the RV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Can be increasing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Size of the LA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>RA&#47;LA ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal &#40;LA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>RA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Interventricular septum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bulges from right to left&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bulges from left to right&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Systolic deceleration of the RV outflow tract&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>E&#47;A ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lateral e&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lateral E&#47;e&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Hemodynamics</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Aortic pressure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal or low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal or high&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PCWP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8804;15<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;5<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PADP&#8211;PCWP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;7<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;5<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Difference between arterial and pulmonary venous hypertension&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; 6MWT&#44; 6-minute walking test&#59; BNP&#44; brain natriuretic peptide&#59; CI&#44; cardiac index&#59; MRI&#44; magnetic resonance imaging&#59; NT-proBNP&#44; amino-terminal fraction of the brain natriuretic propeptide&#59; RAA&#44; right atrial area&#59; RAP&#44; right atrial pressure&#59; SvO<span class="elsevierStyleInf">2</span>&#44; venous oxygen saturation&#59; VO<span class="elsevierStyleInf">2</span>&#44; oxygen consumption&#59; VE&#47;VCO<span class="elsevierStyleInf">2</span>&#44; ventilatory equivalent for carbon dioxide&#59; FC-WHO&#44; functional class of the World Health Organization&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Prognostic factor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Low risk<br>&#40;&#60;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intermediate risk<br>&#40;5&#8211;10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">High risk<br>&#40;&#62;10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clinical signs of right heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Symptom progression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Slow&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fast&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Syncope&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Occasional&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Frequent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FC-WHO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">I</span>&#44; <span class="elsevierStyleSmallCaps">II</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">III</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleSmallCaps">IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6MWT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;440<span class="elsevierStyleHsp" style=""></span>m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">165&#8211;440<span class="elsevierStyleHsp" style=""></span>m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;165<span class="elsevierStyleHsp" style=""></span>m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cardiopulmonary exercise test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peak VO<span class="elsevierStyleInf">2</span><br>&#62;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;kg<br>&#40;&#62;65&#37;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&#41;<br>VE&#47;VCO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peak VO<span class="elsevierStyleInf">2</span><br>11&#8211;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;kg<br>&#40;35&#8211;65&#37;&#41;<br>VE&#47;VCO<span class="elsevierStyleInf">2</span> 36&#8211;44&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peak VO<span class="elsevierStyleInf">2</span><br>&#60;11<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;kg<br>&#40;&#60;35&#37;&#41;<br>VE&#47;VCO<span class="elsevierStyleInf">2</span> &#62;45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NT-proBNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BNP<span class="elsevierStyleHsp" style=""></span>&#60;50<span class="elsevierStyleHsp" style=""></span>ng&#47;L<br>NT-proBNP<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BNP 50&#8211;300<span class="elsevierStyleHsp" style=""></span>ng&#47;L<br>NT-proBNP 300&#8211;1400<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BNP<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>ng&#47;L<br>NT-proBNP<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1400<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Echocardiogram or cardiac MRI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RAA<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>18<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span><br>No pericardial effusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RAA 18&#8211;26<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span><br>Minimal pericardial effusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RAA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>26<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span><br>Pericardial effusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hemodynamic parameters&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RAP<span class="elsevierStyleHsp" style=""></span>&#60;8<span class="elsevierStyleHsp" style=""></span>mmHg<br>CI<span class="elsevierStyleHsp" style=""></span>&#62;2&#46;5<span class="elsevierStyleHsp" style=""></span>L&#47;min&#47;m<span class="elsevierStyleSup">2</span><br>SvO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>65&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RAP 8&#8211;14<span class="elsevierStyleHsp" style=""></span>mmHg<br>CI 2&#8211;2&#46;4<span class="elsevierStyleHsp" style=""></span>L&#47;min&#47;m<span class="elsevierStyleSup">2</span><br>SvO<span class="elsevierStyleInf">2</span> 60&#8211;65&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RAP<span class="elsevierStyleHsp" style=""></span>&#62;14<span class="elsevierStyleHsp" style=""></span>mmHg<br>CI<span class="elsevierStyleHsp" style=""></span>&#60;2&#46;0<span class="elsevierStyleHsp" style=""></span>L&#47;min&#47;m<span class="elsevierStyleSup">2</span><br>SvO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Risk stratification of patients with pulmonary arterial hypertension&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; SC&#44; subcutaneously&#59; IV&#44; intravenously&#59; kg&#44; kilogram&#59; mg&#44; milligram&#59; ng&#44; nanogram&#59; &#956;g&#44; microgram&#59; h&#44; hour&#59; min&#44; minute&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Administration route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse Effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Epoprostenol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Continuous IV perfusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;40<span class="elsevierStyleHsp" style=""></span>ng&#47;kg&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotension&#44; flushing&#44; nausea&#47;vomiting&#44; diarrhea&#44; headache&#44; thrombocytopenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Treprostinil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Continuous IV perfusion<br>Continuous SC perfusion<br><br>Inhaled<br><br>Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;25&#8211;40<span class="elsevierStyleHsp" style=""></span>ng&#47;kg&#47;min<br><br>6<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;inhalation<br><br>3&#8211;9 inhalations in 4 sessions&#47;day<br><br>0&#46;125&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg<br>c&#47;12&#8211;8<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mandibular pain&#44; pain at the injection site&#44; flushing&#44; nausea&#44; vomiting&#44; diarrhea&#44; headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Iloprost&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhaled&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5&#8211;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;inhalation<br><br>3&#8211;9 inhalations in 4 sessions&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cough&#44; syncope&#44; trismus&#44; flushing&#44; nausea&#44; vomiting&#44; diarrhea&#44; headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bosentan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#46;5<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h in month 1&#59; then 125<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatotoxicity&#44; anemia&#44; peripheral edema&#44; angina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ambrisentan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Macitentan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anemia&#44; hypotension&#44; peripheral edema&#44; hepatotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sildenafil&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotension&#44; amaurosis&#44; hearing loss&#44; priapism&#44; vaso-occlusive crisis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tadalafil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypotension&#44; amaurosis&#44; hearing loss&#44; priapism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Riociguat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Headaches&#44; gastritis&#44; dizziness&#44; nausea&#44; vomiting&#44; hypotension&#44; anemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Drugs for treating pulmonary arterial hypertension&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:45 [
            0 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Updated clinical classification of pulmonary hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Simonneau"
                            1 => "M&#46;A&#46; Gatzoulis"
                            2 => "I&#46; Adatia"
                            3 => "D&#46; Celermajer"
                            4 => "C&#46; Denton"
                            5 => "A&#46; Ghofrani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2013.10.029"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2013"
                        "volumen" => "62"
                        "numero" => "Suppl&#46;"
                        "paginaInicial" => "D34"
                        "paginaFinal" => "D41"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24355639"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0235"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary arterial hypertension&#58; yesterday&#44; today&#44; tomorrow"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46;D&#46; Michelakis"
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                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1161/CIRCRESAHA.115.301132"
                      "Revista" => array:6 [
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                        "paginaInicial" => "109"
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                            "web" => "Medline"
                          ]
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                      ]
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                ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2015 ESC&#47;ERS guidelines for the diagnosis and treatment of pulmonary hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Gali&#232;"
                            1 => "M&#46; Humbert"
                            2 => "J&#46;L&#46; Vachiery"
                            3 => "S&#46; Gibbs"
                            4 => "I&#46; Lang"
                            5 => "A&#46; Torbicki"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehv317"
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                        "tituloSerie" => "Eur Heart J"
                        "fecha" => "2016"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary arterial hypertension&#58; from the kingdom of the near-dead to multiple clinical trial meta-analyses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "N&#46; Gali"
                            1 => "M&#46; Palazzini"
                            2 => "A&#46; Manes"
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                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehq152"
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                        "tituloSerie" => "Eur Heart J"
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                        "volumen" => "31"
                        "paginaInicial" => "2080"
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                    0 => array:2 [
                      "titulo" => "Definitions and diagnosis of pulmonary hypertension"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;M&#46; Hoeper"
                            1 => "H&#46;J&#46; Bogaard"
                            2 => "R&#46; Condliffe"
                            3 => "R&#46; Frantz"
                            4 => "D&#46; Khanna"
                            5 => "M&#46; Kurzyna"
                          ]
                        ]
                      ]
                    ]
                  ]
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                      "doi" => "10.1016/j.jacc.2013.10.032"
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                    0 => array:2 [
                      "titulo" => "Diastolic pulmonary vascular pressure gradient&#58; a predictor of prognosis in out-of-proportion pulmonary hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Gerges"
                            1 => "M&#46; Gerges"
                            2 => "M&#46;B&#46; Lang"
                            3 => "Y&#46; Zhang"
                            4 => "J&#46; Jakowitsch"
                            5 => "P&#46; Probst"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.12-1653"
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                        "paginaInicial" => "758"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Borderline mean pulmonary artery pressure in patients with systemic sclerosis&#58; transpulmonary gradient predicts risk of developing pulmonary hypertension"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46;J&#46; Valerio"
                            1 => "B&#46;E&#46; Schreiber"
                            2 => "C&#46;E&#46; Handler"
                            3 => "C&#46;P&#46; Denton"
                            4 => "J&#46;G&#46; Coghlan"
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                    0 => array:2 [
                      "doi" => "10.1002/art.37838"
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                        "fecha" => "2013"
                        "volumen" => "65"
                        "paginaInicial" => "1074"
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                    0 => array:2 [
                      "titulo" => "Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the Reveal Registry"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Chung"
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