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but had a personal history of bipolar affective disorder &#40;long-term treatment regimen consisting of oral lamotrigine 100 mg once daily and risperidone 6 mg once daily&#41; and was a former smoker&#59; she reported no other cardiovascular risk factors&#44; use of anorectic drugs or consumption of toxic oils&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Two-dimensional transthoracic echocardiography showed dilated right heart chambers and signs of elevated pulmonary pressures&#44; with no evidence of atrial septal defect and normal left ventricular systolic&#44; diastolic and valve function&#46; Computed tomography pulmonary angiography &#40;CTPA&#41; confirmed the presence of right heart chamber dilatation &#40;right ventricular end-diastolic diameter of 51 mm&#41; and signs of PH &#40;pulmonary trunk diameter greater than that of the ascending aorta&#41; with no visible pulmonary artery defects&#46; As a result of these findings&#44; the patient was diagnosed with pulmonary arterial hypertension &#40;PAH&#41; and was referred to the specialist PH unit at our center&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">At admission to the PH unit the patient was in a wheelchair and reported WHO functional class III&#8211;IV dyspnea and exercise related-syncope for one year&#46; Physical examination showed normal systolic blood pressure&#44; heart rate and central venous pressure&#44; with basal oxygen saturation of 85&#37;&#46; Auscultation of the heart revealed a loud second cardiac sound with an accompanying audible pulmonary valve regurgitation murmur&#46; No physical signs of heart failure were found and abdominal examination was unremarkable&#46; The electrocardiogram showed normal sinus rhythm&#44; right atrial enlargement and right ventricular hypertrophy with secondary repolarization disturbances&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Subsequent investigations included a new transthoracic echocardiogram&#44; pulmonary function tests &#40;PFTs&#41;&#44; arterial blood gases&#44; full blood count &#40;FBC&#41;&#44; 6MWT and a V&#47;Q scan&#46; The transthoracic echocardiogram showed dilatation of the right heart chambers &#40;right atrial area of 22 cm<span class="elsevierStyleSup">2</span> and right ventricular end-diastolic diameter of 44 mm&#41;&#44; right ventricular wall hypertrophy &#40;10 mm&#41;&#44; right ventricular dysfunction &#40;right myocardial performance index&#58; 0&#46;36&#59; peak tissue Doppler velocity&#58; 8 cm&#47;s&#59; and tricuspid annular plane systolic excursion &#91;TAPSE&#93;&#58; 15 mm&#41;&#44; diastolic dysfunction&#44; normal systolic function with no mitral or aortic valve abnormalities&#44; estimated pulmonary artery systolic pressure &#40;PASP&#41; of 115 mmHg and significantly increased pulmonary vascular resistance &#40;pulmonary acceleration time of 49 ms&#41;&#46; PFTs were carried out with the following results&#58; forced vital capacity &#40;FVC&#41; 97&#37;&#59; forced expiratory volume in 1 s &#40;FEV1&#41; 100&#37;&#59; FEV1&#47;FVC 68&#37;&#59; diffusing capacity of the lung for carbon monoxide &#40;DLCO&#41; 84&#37;&#59; DLCO&#47;alveolar volume 93&#37;&#59; total lung capacity 109&#37;&#59; and residual volume 140&#37;&#46; Arterial blood gas results were&#58; pH 7&#46;41&#59; PaO<span class="elsevierStyleInf">2</span> 48 mmHg&#59; PaCO<span class="elsevierStyleInf">2</span> 35 mmHg&#59; and SpO<span class="elsevierStyleInf">2</span> 83&#37;&#46; FBC was normal&#46; Serum NT-proBNP was significantly raised &#40;1032 pg&#47;ml&#41;&#46; The patient was able to walk a distance of 180 m in the 6MWT without experiencing hypotension or desaturation&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">At this point&#44; a new V&#47;Q scan was performed in order to rule out CTEPH&#44; despite the fact that previous CTPA showed no evidence of pulmonary artery defects&#46; The V&#47;Q scan showed multiple perfusion defects in both lungs&#44; together with normal ventilation &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46; Given the high sensitivity of V&#47;Q scanning for detecting CTEPH&#44; this positive result cast doubt on the original diagnosis&#46; The next step was to perform a new CTPA&#44; which now showed involvement of the left distal segmental arteries and the distal segmental branches of the right superior&#44; mid and inferior lobar arteries &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Following a review of the results&#44; the diagnosis was reconsidered and changed from PAH to CTEPH&#44; confirmed by right heart catheterization and pulmonary angiography&#46; Pulmonary angiography demonstrated the presence of very distal thrombotic occlusions and findings on right heart catheterization were compatible with CTEPH &#40;mean right atrial pressure&#58; 9 mmHg&#59; right ventricular pressure&#58; 135&#47;19 mmHg&#59; pulmonary artery pressure&#58; 135&#47;37 mmHg&#59; mean pulmonary artery pressure&#58; 72 mmHg&#59; pulmonary capillary wedge pressure&#58; 8 mmHg&#59; cardiac output&#58; 3&#46;97 l&#47;min&#59; cardiac index&#58; 2&#46;64 l&#47;min&#47;m<span class="elsevierStyleSup">2</span>&#59; pulmonary vascular resistance&#58; 3 Wood units&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The case was discussed with the specialist CTEPH team and the patient was considered unsuitable for PEA due to very distal involvement &#40;University of California-San Diego surgical classification type III&#41;&#46; Due to the lack of efficacy of classic vasodilators &#40;endothelin receptor antagonists&#44; phosphodiesterase inhibitors&#44; and prostacyclins&#41; in CTEPH&#44; new therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled early access study for treatment with riociguat &#40;an oral soluble guanylate cyclase stimulator&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient was started on a dose of 1 mg riociguat tid&#46; The dose was increased by 0&#46;5 mg tid every two weeks and any adverse events were reported&#46; The maximum dose of riociguat &#40;2&#46;5 mg tid&#41; was reached at visit 4 &#40;week 6&#41;&#44; in accordance with the study protocol&#46; At this time the patient was in functional class III&#46; At week 12&#44; the patient reported that she was able to walk 200 m without effort&#44; but that she had experienced an episode of exercise-related presyncope&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">After three months on the maximum 2&#46;5 mg tid dose of riociguat&#44; the patient was able to attend her hospital check-up without wheelchair assistance or any other aids&#46; At this visit&#44; the patient had a 6MWT of 255 m and a Borg dyspnea index of 7&#44; and was in functional class II&#46; Between check-ups&#44; she had not experienced new exercise-related syncope episodes&#44; and no riociguat-related adverse events were reported&#46; The patient was assessed again nine months after beginning riociguat treatment&#44; at which time she walked 300 m during her 6MWT and had a Borg dyspnea score of 2&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">At the last visit&#44; one year after beginning riociguat treatment&#44; the patient was in functional class II&#44; and was able to walk 345 m during the 6MWT&#46; She had suffered a new syncope episode in the context of severe anemia &#40;hemoglobin 8&#46;1 g&#47;dl&#41; due to gynecological bleeding&#44; needing blood transfusion&#46; Serum NT-proBNP was 367&#46;3 pg&#47;ml &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41; and she showed no clinical signs of heart failure&#46; Repeat transthoracic echocardiography was performed&#44; and showed right chamber dilatation &#40;right atrial area 22 cm<span class="elsevierStyleSup">2</span> and right ventricular end-diastolic diameter 40 mm&#41;&#44; right ventricular systolic dysfunction &#40;right myocardial performance index&#58; 0&#46;52&#44; peak tissue velocity&#58; 9 cm&#47;s and TAPSE 17 mm&#41; and PASP of 82 mmHg&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">CTEPH is a disease caused by chronic obstruction of the pulmonary vasculature&#44; which can occur in both the proximal and distal pulmonary arteries&#46; CTEPH represents Group 4 in the recent WHO clinical classification of PH&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> CTEPH is defined as PH confirmed by right heart catheterization &#40;mean pulmonary artery pressure &#8805;25 mmHg and pulmonary artery wedge pressure &#8804;15 mmHg&#41;&#44; with the presence of chronic thrombi in the elastic pulmonary arteries after at least three months of anticoagulation therapy&#46; Although the incidence of CTEPH is relatively low&#44; it remains one of the most common subsets of precapillary PH&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">A number of risk factors have been identified for CTEPH&#44; including previous splenectomy&#44; hematological disorders &#40;antithrombin deficiency&#44; protein C and S deficiency&#44; factor V Leiden&#44; plasminogen deficiency&#44; anticardiolipin and antiphospholipid antibodies&#44; and lupus anticoagulant&#41;&#44; ventriculoatrial shunts for treatment of hydrocephalus&#44; indwelling catheters&#44; cancer&#44; treatment of hypothyroidism&#44; and chronic inflammatory disorders&#46; The clinical signs and symptoms of CTEPH are nonspecific and the diagnosis is therefore often delayed &#40;with a median of 14 months to diagnosis from the onset of symptoms&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> V&#47;Q scanning is the technique of choice when screening for CTEPH&#44; due to its high sensitivity &#40;&#62;96&#37;&#41;&#46; This means that a normal V&#47;Q scan essentially rules out CTEPH&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> Other useful diagnostic tools include CTPA and pulmonary arteriography&#44; although they have lower sensitivity&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">To date&#44; the only potentially curative treatment for CTEPH is PEA&#44; a surgical intervention with perioperative mortality rates of between &#60;2&#37; and 5&#37; in experienced centers&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> In patients with inoperable CTEPH&#44; balloon pulmonary angioplasty has been the subject of some research interest as a potential therapeutic option<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a>&#59; however&#44; this technique requires further evaluation and has yet to become established&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> Bilateral lung or heart&#47;lung transplantation&#44; while potentially curative&#44; is limited to young patients with no other treatment options&#46; Until recently&#44; the only available medical therapies for patients with inoperable CTEPH were oxygen therapy and lifelong oral anticoagulation&#46; Pulmonary vasodilators&#44; such as endothelin receptor antagonists&#44; phosphodiesterase inhibitors&#44; and prostacyclins&#44; have not shown significant efficacy in patients with CTEPH in randomized trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">7&#44;8</span></a> There is&#44; however&#44; a novel and promising pharmacological treatment&#44; the oral soluble guanylate cyclase stimulator riociguat&#46; In the recent phase III CHEST-1 trial&#44; riociguat improved 6MWT&#44; WHO functional class&#44; NT-proBNP levels&#44; and hemodynamic parameters in patients with CTEPH&#44; with a good safety profile&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a> Riociguat is the first drug approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of CTEPH&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In this case report we show the clinical outcomes and safety profile of this new therapeutic agent in non-operable CTEPH cases&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical disclosures</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of human and animal subjects</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee&#44; with those of the Code of Ethics of the World Medical Association &#40;Declaration of Helsinki&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Confidentiality of data</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Author contributions</span><p id="par0095" class="elsevierStylePara elsevierViewall">Prof&#46; Gomez-Sanchez&#44; Dr&#46; Ortiz-Bautista&#44; Dr&#46; Navas-Tejedor&#44; Dr&#46; Mor&#225;n-Fern&#225;ndez and Nuria Ochoa-Parra wrote the case report and prepared the manuscript&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">Professor G&#243;mez-S&#225;nchez has received speaker fees&#44; honoraria&#44; consultancy&#44; advisory board fees&#44; investigator&#44; committee member&#44; etc&#46; from Bayer&#44; Actelion&#44; Pfizer&#44; GSK and Ferrer Pharma&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A 51-year-old woman presented with a one-year history of progressive dyspnea&#44; WHO functional class III-IV and exercise-related syncope&#46; Transthoracic echocardiography and computed tomography pulmonary angiography were performed&#44; leading to a diagnosis of pulmonary arterial hypertension&#46; She was referred to our pulmonary hypertension unit&#44; where a complete study was performed&#44; including ventilation&#47;perfusion scan&#44; which was consistent with chronic thromboembolic pulmonary hypertension&#46; Risk factors for this condition were excluded and therapeutic options were evaluated&#46; Imaging studies showed distal pulmonary disease so pulmonary endarterectomy was rejected&#46; Further therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled trial with riociguat&#46; After one year of treatment&#44; significant improvement in functional class&#44; 6-minute walk test and NT-proBNP were seen&#44; without significant secondary effects&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Uma mulher de 51 anos de idade apresentou-se com hist&#243;ria de um ano de dispneia progressiva com classe funcional III-IV e s&#237;ncope relacionada com exerc&#237;cio&#46; A ecocardiografia transtor&#225;cica e a angiotomografia pulmonar computadorizada foram realizadas&#44; tendo sido diagnosticada hipertens&#227;o arterial pulmonar&#46; A doente foi encaminhada para a Unidade de Hipertens&#227;o Pulmonar&#44; onde foi repetido o estudo completo&#44; incluindo verifica&#231;&#227;o de ventila&#231;&#227;o&#47;perfus&#227;o&#44; compat&#237;vel com hipertens&#227;o pulmonar tromboemb&#243;lica cr&#243;nica&#46; Os fatores de risco para essa situa&#231;&#227;o foram exclu&#237;dos e foram avaliadas as op&#231;&#245;es terap&#234;uticas&#46; Estudos de imagem mostraram doen&#231;a pulmonar distal pelo que a endarterectomia pulmonar foi rejeitada&#46; Foram avaliadas novas op&#231;&#245;es terap&#234;uticas e a doente foi posteriormente inscrita num estudo aberto&#44; n&#227;o controlado&#44; com ensaio com riociguat&#46; Ap&#243;s um ano de tratamento&#44; uma melhoria significativa na classe funcional&#44; um teste de caminhada de 6 minutos e NT-proBNP foram alcan&#231;ados sem efeitos secund&#225;rios significativos&#46;</p></span>"
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                      "titulo" => "Update on chronic thromboembolic pulmonary hypertension"
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Case report
Inoperable chronic thromboembolic pulmonary hypertension treated with riociguat: A case study
Hipertensão pulmonar tromboembólica crónica inoperável tratada com riociguat: um caso clínico
Carlos Ortiz-Bautistaa, Nuria Ochoa-Parrab, Paula Navas-Tejedorb, Laura Morán-Fernándezb, Miguel Ángel Gómez-Sánchezb,
Autor para correspondência
mgomezsanchez@salud.madrid.org

Corresponding author.
a Department of Cardiology, Institute of Heart Sciences (ICICOR), Hospital Clinico Universitario, Valladolid, Spain
b Multidisciplinary Pulmonary Hypertension Unit, Cardiology Service, Hospital Universitario 12 de Octubre, CIBERES, Madrid, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic thromboembolic pulmonary hypertension &#40;CTEPH&#41; is an uncommon disease characterized by obstruction of the pulmonary vasculature by residual organized thrombi&#44; leading to increased pulmonary vascular resistance&#44; progressive pulmonary hypertension &#40;PH&#41; and&#44; in its final stages&#44; right ventricular failure&#46; A ventilation&#47;perfusion &#40;V&#47;Q&#41; scan is mandatory for the screening of this condition&#46; Long-term prognosis of patients with CTEPH is poor unless they receive treatment early&#46; Pulmonary endarterectomy &#40;PEA&#41; is the treatment of choice for CTEPH and is the only potentially curative intervention&#44; with low perioperative mortality in experienced centers&#46; Previously&#44; treatment options for patients ineligible for pulmonary endarterectomy were limited to off-label treatment with pulmonary vasodilators&#44; balloon pulmonary angioplasty&#44; and lung transplantation&#46; However&#44; riociguat&#44; a novel oral soluble guanylate-cyclase stimulator&#44; was recently shown to be an effective treatment option for patients with inoperable CTEPH&#44; with improvements in prognostic variables such as the 6-minute walk test &#40;6MWT&#41;&#44; World Health Organization &#40;WHO&#41; functional class and N-terminal pro-brain natriuretic peptide &#40;NT-proBNP&#41;&#46; We present a case of inoperable CTEPH treated with riociguat&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case report</span><p id="par0010" class="elsevierStylePara elsevierViewall">A 51-year-old woman presented with a one-year history of progressive dyspnea and exercise-related syncope&#46; The patient had no drug allergies or family history of note&#44; but had a personal history of bipolar affective disorder &#40;long-term treatment regimen consisting of oral lamotrigine 100 mg once daily and risperidone 6 mg once daily&#41; and was a former smoker&#59; she reported no other cardiovascular risk factors&#44; use of anorectic drugs or consumption of toxic oils&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Two-dimensional transthoracic echocardiography showed dilated right heart chambers and signs of elevated pulmonary pressures&#44; with no evidence of atrial septal defect and normal left ventricular systolic&#44; diastolic and valve function&#46; Computed tomography pulmonary angiography &#40;CTPA&#41; confirmed the presence of right heart chamber dilatation &#40;right ventricular end-diastolic diameter of 51 mm&#41; and signs of PH &#40;pulmonary trunk diameter greater than that of the ascending aorta&#41; with no visible pulmonary artery defects&#46; As a result of these findings&#44; the patient was diagnosed with pulmonary arterial hypertension &#40;PAH&#41; and was referred to the specialist PH unit at our center&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">At admission to the PH unit the patient was in a wheelchair and reported WHO functional class III&#8211;IV dyspnea and exercise related-syncope for one year&#46; Physical examination showed normal systolic blood pressure&#44; heart rate and central venous pressure&#44; with basal oxygen saturation of 85&#37;&#46; Auscultation of the heart revealed a loud second cardiac sound with an accompanying audible pulmonary valve regurgitation murmur&#46; No physical signs of heart failure were found and abdominal examination was unremarkable&#46; The electrocardiogram showed normal sinus rhythm&#44; right atrial enlargement and right ventricular hypertrophy with secondary repolarization disturbances&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Subsequent investigations included a new transthoracic echocardiogram&#44; pulmonary function tests &#40;PFTs&#41;&#44; arterial blood gases&#44; full blood count &#40;FBC&#41;&#44; 6MWT and a V&#47;Q scan&#46; The transthoracic echocardiogram showed dilatation of the right heart chambers &#40;right atrial area of 22 cm<span class="elsevierStyleSup">2</span> and right ventricular end-diastolic diameter of 44 mm&#41;&#44; right ventricular wall hypertrophy &#40;10 mm&#41;&#44; right ventricular dysfunction &#40;right myocardial performance index&#58; 0&#46;36&#59; peak tissue Doppler velocity&#58; 8 cm&#47;s&#59; and tricuspid annular plane systolic excursion &#91;TAPSE&#93;&#58; 15 mm&#41;&#44; diastolic dysfunction&#44; normal systolic function with no mitral or aortic valve abnormalities&#44; estimated pulmonary artery systolic pressure &#40;PASP&#41; of 115 mmHg and significantly increased pulmonary vascular resistance &#40;pulmonary acceleration time of 49 ms&#41;&#46; PFTs were carried out with the following results&#58; forced vital capacity &#40;FVC&#41; 97&#37;&#59; forced expiratory volume in 1 s &#40;FEV1&#41; 100&#37;&#59; FEV1&#47;FVC 68&#37;&#59; diffusing capacity of the lung for carbon monoxide &#40;DLCO&#41; 84&#37;&#59; DLCO&#47;alveolar volume 93&#37;&#59; total lung capacity 109&#37;&#59; and residual volume 140&#37;&#46; Arterial blood gas results were&#58; pH 7&#46;41&#59; PaO<span class="elsevierStyleInf">2</span> 48 mmHg&#59; PaCO<span class="elsevierStyleInf">2</span> 35 mmHg&#59; and SpO<span class="elsevierStyleInf">2</span> 83&#37;&#46; FBC was normal&#46; Serum NT-proBNP was significantly raised &#40;1032 pg&#47;ml&#41;&#46; The patient was able to walk a distance of 180 m in the 6MWT without experiencing hypotension or desaturation&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">At this point&#44; a new V&#47;Q scan was performed in order to rule out CTEPH&#44; despite the fact that previous CTPA showed no evidence of pulmonary artery defects&#46; The V&#47;Q scan showed multiple perfusion defects in both lungs&#44; together with normal ventilation &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46; Given the high sensitivity of V&#47;Q scanning for detecting CTEPH&#44; this positive result cast doubt on the original diagnosis&#46; The next step was to perform a new CTPA&#44; which now showed involvement of the left distal segmental arteries and the distal segmental branches of the right superior&#44; mid and inferior lobar arteries &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Following a review of the results&#44; the diagnosis was reconsidered and changed from PAH to CTEPH&#44; confirmed by right heart catheterization and pulmonary angiography&#46; Pulmonary angiography demonstrated the presence of very distal thrombotic occlusions and findings on right heart catheterization were compatible with CTEPH &#40;mean right atrial pressure&#58; 9 mmHg&#59; right ventricular pressure&#58; 135&#47;19 mmHg&#59; pulmonary artery pressure&#58; 135&#47;37 mmHg&#59; mean pulmonary artery pressure&#58; 72 mmHg&#59; pulmonary capillary wedge pressure&#58; 8 mmHg&#59; cardiac output&#58; 3&#46;97 l&#47;min&#59; cardiac index&#58; 2&#46;64 l&#47;min&#47;m<span class="elsevierStyleSup">2</span>&#59; pulmonary vascular resistance&#58; 3 Wood units&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The case was discussed with the specialist CTEPH team and the patient was considered unsuitable for PEA due to very distal involvement &#40;University of California-San Diego surgical classification type III&#41;&#46; Due to the lack of efficacy of classic vasodilators &#40;endothelin receptor antagonists&#44; phosphodiesterase inhibitors&#44; and prostacyclins&#41; in CTEPH&#44; new therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled early access study for treatment with riociguat &#40;an oral soluble guanylate cyclase stimulator&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient was started on a dose of 1 mg riociguat tid&#46; The dose was increased by 0&#46;5 mg tid every two weeks and any adverse events were reported&#46; The maximum dose of riociguat &#40;2&#46;5 mg tid&#41; was reached at visit 4 &#40;week 6&#41;&#44; in accordance with the study protocol&#46; At this time the patient was in functional class III&#46; At week 12&#44; the patient reported that she was able to walk 200 m without effort&#44; but that she had experienced an episode of exercise-related presyncope&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">After three months on the maximum 2&#46;5 mg tid dose of riociguat&#44; the patient was able to attend her hospital check-up without wheelchair assistance or any other aids&#46; At this visit&#44; the patient had a 6MWT of 255 m and a Borg dyspnea index of 7&#44; and was in functional class II&#46; Between check-ups&#44; she had not experienced new exercise-related syncope episodes&#44; and no riociguat-related adverse events were reported&#46; The patient was assessed again nine months after beginning riociguat treatment&#44; at which time she walked 300 m during her 6MWT and had a Borg dyspnea score of 2&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">At the last visit&#44; one year after beginning riociguat treatment&#44; the patient was in functional class II&#44; and was able to walk 345 m during the 6MWT&#46; She had suffered a new syncope episode in the context of severe anemia &#40;hemoglobin 8&#46;1 g&#47;dl&#41; due to gynecological bleeding&#44; needing blood transfusion&#46; Serum NT-proBNP was 367&#46;3 pg&#47;ml &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41; and she showed no clinical signs of heart failure&#46; Repeat transthoracic echocardiography was performed&#44; and showed right chamber dilatation &#40;right atrial area 22 cm<span class="elsevierStyleSup">2</span> and right ventricular end-diastolic diameter 40 mm&#41;&#44; right ventricular systolic dysfunction &#40;right myocardial performance index&#58; 0&#46;52&#44; peak tissue velocity&#58; 9 cm&#47;s and TAPSE 17 mm&#41; and PASP of 82 mmHg&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">CTEPH is a disease caused by chronic obstruction of the pulmonary vasculature&#44; which can occur in both the proximal and distal pulmonary arteries&#46; CTEPH represents Group 4 in the recent WHO clinical classification of PH&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> CTEPH is defined as PH confirmed by right heart catheterization &#40;mean pulmonary artery pressure &#8805;25 mmHg and pulmonary artery wedge pressure &#8804;15 mmHg&#41;&#44; with the presence of chronic thrombi in the elastic pulmonary arteries after at least three months of anticoagulation therapy&#46; Although the incidence of CTEPH is relatively low&#44; it remains one of the most common subsets of precapillary PH&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">A number of risk factors have been identified for CTEPH&#44; including previous splenectomy&#44; hematological disorders &#40;antithrombin deficiency&#44; protein C and S deficiency&#44; factor V Leiden&#44; plasminogen deficiency&#44; anticardiolipin and antiphospholipid antibodies&#44; and lupus anticoagulant&#41;&#44; ventriculoatrial shunts for treatment of hydrocephalus&#44; indwelling catheters&#44; cancer&#44; treatment of hypothyroidism&#44; and chronic inflammatory disorders&#46; The clinical signs and symptoms of CTEPH are nonspecific and the diagnosis is therefore often delayed &#40;with a median of 14 months to diagnosis from the onset of symptoms&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> V&#47;Q scanning is the technique of choice when screening for CTEPH&#44; due to its high sensitivity &#40;&#62;96&#37;&#41;&#46; This means that a normal V&#47;Q scan essentially rules out CTEPH&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> Other useful diagnostic tools include CTPA and pulmonary arteriography&#44; although they have lower sensitivity&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">To date&#44; the only potentially curative treatment for CTEPH is PEA&#44; a surgical intervention with perioperative mortality rates of between &#60;2&#37; and 5&#37; in experienced centers&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> In patients with inoperable CTEPH&#44; balloon pulmonary angioplasty has been the subject of some research interest as a potential therapeutic option<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a>&#59; however&#44; this technique requires further evaluation and has yet to become established&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> Bilateral lung or heart&#47;lung transplantation&#44; while potentially curative&#44; is limited to young patients with no other treatment options&#46; Until recently&#44; the only available medical therapies for patients with inoperable CTEPH were oxygen therapy and lifelong oral anticoagulation&#46; Pulmonary vasodilators&#44; such as endothelin receptor antagonists&#44; phosphodiesterase inhibitors&#44; and prostacyclins&#44; have not shown significant efficacy in patients with CTEPH in randomized trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">7&#44;8</span></a> There is&#44; however&#44; a novel and promising pharmacological treatment&#44; the oral soluble guanylate cyclase stimulator riociguat&#46; In the recent phase III CHEST-1 trial&#44; riociguat improved 6MWT&#44; WHO functional class&#44; NT-proBNP levels&#44; and hemodynamic parameters in patients with CTEPH&#44; with a good safety profile&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a> Riociguat is the first drug approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of CTEPH&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In this case report we show the clinical outcomes and safety profile of this new therapeutic agent in non-operable CTEPH cases&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical disclosures</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of human and animal subjects</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee&#44; with those of the Code of Ethics of the World Medical Association &#40;Declaration of Helsinki&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Confidentiality of data</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Author contributions</span><p id="par0095" class="elsevierStylePara elsevierViewall">Prof&#46; Gomez-Sanchez&#44; Dr&#46; Ortiz-Bautista&#44; Dr&#46; Navas-Tejedor&#44; Dr&#46; Mor&#225;n-Fern&#225;ndez and Nuria Ochoa-Parra wrote the case report and prepared the manuscript&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">Professor G&#243;mez-S&#225;nchez has received speaker fees&#44; honoraria&#44; consultancy&#44; advisory board fees&#44; investigator&#44; committee member&#44; etc&#46; from Bayer&#44; Actelion&#44; Pfizer&#44; GSK and Ferrer Pharma&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A 51-year-old woman presented with a one-year history of progressive dyspnea&#44; WHO functional class III-IV and exercise-related syncope&#46; Transthoracic echocardiography and computed tomography pulmonary angiography were performed&#44; leading to a diagnosis of pulmonary arterial hypertension&#46; She was referred to our pulmonary hypertension unit&#44; where a complete study was performed&#44; including ventilation&#47;perfusion scan&#44; which was consistent with chronic thromboembolic pulmonary hypertension&#46; Risk factors for this condition were excluded and therapeutic options were evaluated&#46; Imaging studies showed distal pulmonary disease so pulmonary endarterectomy was rejected&#46; Further therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled trial with riociguat&#46; After one year of treatment&#44; significant improvement in functional class&#44; 6-minute walk test and NT-proBNP were seen&#44; without significant secondary effects&#46;</p></span>"
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