2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).

Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk-benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.

Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study.

BACKGROUND: By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. CONCLUSIONS: Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).

[Updated clinical classification of pulmonary hypertension]. / Pulmoner arter hipertansiyonunun güncel klinik siniflandirilmasi.

In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (YPPH) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1". Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4. (J Am Coll Cardiol 2013;62:D34-41) a 2013 by the American College of Cardiology Foundation.

Safety of inhaled nitric oxide withdrawal in severe chronic pulmonary hypertension.

Inhaled nitric oxide (iNO) is a potent and selective pulmonary vasodilator with a safety concern due to rebound pulmonary hypertension (PH) associated with its withdrawal. We report short-term pulsed iNO in patients with severe pulmonary arterial hypertension (PAH) and nonoperable chronic thromboembolic PH (nCTEPH). This is a retrospective analysis of 33 patients: 22 with PAH and 11 with nCTEPH. We assessed hemodynamic, echocardiographic, and other noninvasive variables to evaluate safety and efficacy of iNO. We performed an iNO withdrawal test during right heart catheterization and after 3 days of iNO treatment. iNO significantly improved all variables examined in 22 patients with PAH and 11 with nCTEPH. Two patterns of response were observed after sudden iNO withdrawal. Twenty-nine patients (88%) showed minimal hemodynamic, oxygenation and clinical changes. Four patients (12%) had a reduction in cardiac index ≥20% and PaO2 ≥ 5%, three patients did not show clinical deterioration, and one patient developed hemodynamic collapse that needed iNO administration. This retrospective study suggests that short-term iNO improves hemodynamics and clinical conditions in some patients with PAH an nCTPEH. However, pulsed iNO withdrawal PH rebound could be a serious concern in these patients. Given the lack of evidence, we do not recommend the use of pulsed iNO in the treatment of patients with chronic PH.

Bone loss after heart transplant: effect of alendronate, etidronate, calcitonin, and calcium plus vitamin D3.

OBJECTIVE: To compare the effects of calcitonin, etidronate, and alendronate in preventing bone loss during the first 2 years after heart transplant. METHODS: A total of 222 heart transplant recipients (mean [SD] age, 52.4 [10] years, 85% male) were evaluated. Patients with normal bone mineral density (reference group, n = 102) received 1000 mg/d calcium plus 800 IU/d vitamin D3. The rest were assigned to 200 IU/d of calcitonin (n=42), 400 mg/d etidronate orally for 14 days quarterly (n = 33), or 10 mg/d alendronate (n = 45). All patients received calcium and vitamin D. Bone mineral density was assessed by dual-energy x-ray absorptiometry in the lumbar spine, the entire femur, and the femoral neck at baseline and 6, 12, and 24 months after transplant. RESULTS: At 2 years after transplant, bone mineral density in the lumbar spine had decreased in the reference group (-3.07%), calcitonin group (-0.93%), and etidronate group (-1.87%) but not in the alendronate group (+4.9%; P <.001). After 2 years, bone mineral density in the entire femur decreased in all groups (-3.2% in the reference group, -3.6% in the calcitonin group, -4.6% in the etidronate group, and -0.5% in the alendronate group) but bone loss was significantly lower in the alendronate group (P <.001). Bone mineral density in the femoral neck also decreased in all groups. The incidence of vertebral fractures did not differ among groups. Adverse events were similar between groups. CONCLUSIONS: Alendronate therapy in heart transplant recipients was associated with a significant increase in bone mineral density in the lumbar spine and less bone loss at the hip.

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry.

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. RESULTS: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. CONCLUSION: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry.

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. RESULTS: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). CONCLUSION: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.

Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Summary of Recommendations. / Guía de diagnóstico y tratamiento de la hipertensión pulmonar: resumen de recomendaciones.

Pulmonary hypertension is a hemodynamic disorder defined by abnormally high pulmonary artery pressure that can occur in numerous diseases and clinical situations. The causes of pulmonary hypertension are classified into 5 major groups: arterial, due to left heart disease, due to lung disease and/or hypoxemia, chronic thromboembolic, with unclear and/or multifactorial mechanisms. This is a brief summary of the Guidelines on the Diagnostic and Treatment of Pulmonary Hypertension of the Spanish Society of Pulmonology and Thoracic Surgery. These guidelines describe the current recommendations for the diagnosis and treatment of the different pulmonary hypertension groups.

Trends in Pulmonary Hypertension Over a Period of 30 Years: Experience From a Single Referral Centre.

INTRODUCTION AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, right ventricular dysfunction and death. Despite scientific advances, is still associated with high morbidity and mortality. The aim is to describe the clinical approach and determine the prognostic factors of patients with PAH treated in a national reference center over 30 years. METHODS: Three hundred and seventy nine consecutive patients with PAH (January 1984 to December 2014) were studied. Were divided into 3 periods of time: before 2004, 2004-2009 and 2010-2014. Prognostic factors (multivariate analysis) were analyzed for clinical deterioration. RESULTS: Median age was 44 years (68.6% women), functional class III-IV: 72%. An increase was observed in more complex etiologies in the last period of time: Pulmonary venooclusive disease and portopulmonary hypertension. Upfront combination therapy significantly increased (5% before 2004 vs 27% after 2010; P < .05). Multivariate analysis showed prognostic significance in age, sex, etiology and combined clinical variables as they are independent predictors of clinical deterioration (P < .05). Survival free from death or transplantation for the 1st, 3rd and 5th year was 92.2%, 80.6% and 68.5% respectively. The median survival was 9 years (95% confidence interval, 7.532-11.959) CONCLUSIONS: The PAH is a heterogeneous and complex disease, the median survival free from death or transplantation in our series is 9 years after diagnosis. The structure of a multidisciplinary unit PAH must adapt quickly to changes that occur over time incorporating new diagnostic and therapeutic techniques.

Pulmonary Arterial Hypertension in Systemic Lupus Erythematosus: Prevalence and Predictors.

OBJECTIVE: Pulmonary arterial hypertension (PAH) prevalence has been reported to be between 0.5% and 17% in systemic lupus erythematosus (SLE). This study assessed PAH prevalence and predictors in an SLE cohort. METHODS: The Borg dyspnea scale, DLCO, N-terminal pro-brain natriuretic peptide (NT-proBNP), and Doppler echocardiographic (DE) were performed. An echocardiographic Doppler exercise test was conducted in selected patients. When DE systolic pulmonary arterial pressure was ≥ 45 mmHg or increased during exercise > 20 mmHg, a right heart catheterization was performed. Hemodynamic during exercise was measured if rest mean pulmonary arterial pressure was < 25 mmHg. RESULTS: Of the 203 patients with SLE, 152 were included. The mean age was 44.9 ± 12.3 years, and 94% were women. Three patients had known PAH. The algorithm diagnosed 1 patient with chronic thromboembolic pulmonary hypertension and 5 with exercise-induced pulmonary artery pressure increase (4 with occult left diastolic dysfunction). These patients had significantly more dyspnea, higher NT-proBNP, and lower DLCO. CONCLUSION: These data confirm the low prevalence of PAH in SLE. In our cohort, occult left ventricular diastolic dysfunction was a frequent diagnosis of unexplained dyspnea. Dyspnea, DLCO, and NT-proBNP could be predictors of pulmonary hypertension in patients with SLE.

[Pulmonary hypertension during exercise in toxic oil syndrome]. / Hipertensión pulmonar con el ejercicio en el síndrome del aceite tóxico.

BACKGROUND AND OBJECTIVE: Toxic oil syndrome is a risk factor for pulmonary arterial hypertension (PAH) and new cases of this entity are emerging after more than 20 years since the initial toxic oil epidemic. Abnormal elevation of pulmonary systolic pressure with exercise may be considered an early marker of PAH in populations at risk. We aimed to analyze the pulmonary systolic pressure with exercise echocardiography in toxic oil syndrome patients. PATIENTS AND METHOD: 50 toxic oil syndrome patients (cases), and 20 healthy control subjects were submitted to rest and peak exercise echocardiography (semi supine cycloergometer) measuring pulmonary systolic pressure. In toxic oil syndrome patients, pulmonary carbon monoxide diffusion capacity was also analyzed. RESULTS: Peak exercise pulmonary systolic pressure was statistically similar in cases and controls. Nevertheless, 8% of cases reached a pulmonary systolic pressure > or = 80 mmHg and this fact was associated with mild pulmonary arterial hypertension, reduced right ventricular function and abnormal pulmonary diffusion capacity in the rest study. A rest pulmonary systolic pressure cut-off value > or = 27 mmHg had a 100% sensitivity and 71% specificity to predict a peak exercise systolic pulmonary pressure > or = 80 mmHg. CONCLUSIONS: A minority of toxic oil syndrome patients develop severe pulmonary arterial hypertension during exercise. This abnormal response is associated with other markers of pulmonary vasculopathy. Further studies are needed to elucidate the relation between these findings and the likelihood to develop pulmonary arterial hypertension in the future.

Inoperable chronic thromboembolic pulmonary hypertension treated with riociguat: A case study.

A 51-year-old woman presented with a one-year history of progressive dyspnea, WHO functional class III-IV and exercise-related syncope. Transthoracic echocardiography and computed tomography pulmonary angiography were performed, leading to a diagnosis of pulmonary arterial hypertension. She was referred to our pulmonary hypertension unit, where a complete study was performed, including ventilation/perfusion scan, which was consistent with chronic thromboembolic pulmonary hypertension. Risk factors for this condition were excluded and therapeutic options were evaluated. Imaging studies showed distal pulmonary disease so pulmonary endarterectomy was rejected. Further therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled trial with riociguat. After one year of treatment, significant improvement in functional class, 6-minute walk test and NT-proBNP were seen, without significant secondary effects.

Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of long-term morbidity and mortality after heart transplantation (HTx), whose relationship with CMV infection is uncertain. This study evaluated the influence of CMV infection in the development of CAV. METHODS: We enrolled 166 consecutive HTx recipients who underwent their first transplant from January 1995 to July 2002. All patients received 14 days of intravenous ganciclovir and were prospectively monitored for CMV infection during the first year after HTx. CAV was diagnosed by coronary angiography performed at 1, 5, and 10 years after HTx, following the new criteria of the International Society for Heart and Lung Transplantation. We collected all variables potentially related with the development of CAV. Risk factors were studied using a complementary log-log model. RESULTS: After a median follow-up of 11 years (range, 1-17 years), 72 patients (43%) developed CAV (63.8% CAV(1), 15.2% CAV(2), 20.8% CAV(3)). Symptoms secondary to CAV were present in 32% of these patients, and 8% died because of it. In the regression multivariate analysis, independent variables associated with the development of CAV were donor age (hazard ratio [HR], 1.028; 95% confidence interval [CI], 1.002-1.053; p < 0.028), presence of cellular acute rejection ≥ 2R (HR, 1.764; 95% CI, 1.011-3.078; p < 0.0414), CMV infection (HR, 2.334; 95% CI, 1.043-5.225; p < 0.0354), and not having been treated with a calcium channel blocker (HR, 0.472; 95% CI, 0.275-0.811; p < 0.0055). CONCLUSIONS: Standardized angiographic criteria show CMV infection is associated with the development of CAV.

Pulmonary thromboendarterectomy in 106 patients with chronic thromboembolic pulmonary hypertension.

INTRODUCTION: Pulmonary thromboendarterectomy is the treatment of choice in chronic thromboembolic pulmonary hypertension. We report our experience with this technique. METHODS: Between February 1996 and June 2014, we performed 106 pulmonary thromboendarterectomies. Patient population, morbidity and mortality and the long-term results of this technique (survival, functional improvement and resolution of pulmonary hypertension) are described. RESULTS: Subjects' mean age was 53±14 years. A total of 89% were WHO functional class III-IV, presurgery mean pulmonary pressure was 49±13mmHg and mean pulmonary vascular resistance was 831±364 dynes.s.cm(-5). In-hospital mortality was 6.6%. The most important post-operative morbidity was reperfusion pulmonary injury, in 20% of patients; this was an independent risk factor (p=0.015) for hospital mortality. With a 31-month median follow-up (interquartile range: 50), 3- and 5-year survival was 90 and 84%. At 1 year, 91% were WHO functional class I-II; mean pulmonary pressure (27±11mmHg) and pulmonary vascular resistance (275±218 dynes.s.cm(-5)) were significantly lower (p<0.05) than before the intervention. Although residual pulmonary hypertension was detected in 14 patients, their survival at 3 and 5 years was 91 and 73%, respectively. CONCLUSIONS: Pulmonary thromboendarterectomy offers excellent results in chronic thromboembolic pulmonary hypertension. Long-term survival is good, functional capacity improves, and pulmonary hypertension is resolved in most patients.

[Ten years' experience in continuous intravenous epoprostenol therapy in severe pulmonary arterial hypertension]. / Experiencia de 10 años en el tratamiento con epoprostenol en perfusión intravenosa continua en hipertensión pulmonar arterial grave.

INTRODUCTION: Primary pulmonary hypertension and its associated forms is a progressive and often fatal disease, the course of which has been favourably modified by prostacyclin therapy in the last decade. OBJECTIVE: The aim of this study is to analize retrospectively the efficacy of continuous intravenous epoprostenol (synthetic prostacyclin) therapy in pulmonary arterial hypertension, and to compare it with conventional therapy (anticoagulants, digoxin and diuretics). METHODS: Between 1990-2000, 31 patients with severe precapillary pulmonary hypertension in functional class III or IV went on continuous intravenous epoprostenol therapy, administered by a portable infusion pump through a Hickman catheter. We compared their survival with a group of 16 patients treated with conventional therapy alone. RESULTS: Time of follow-up was 33.25 months in the prostacyclin group and 20 months in the conventional group. The one- three- and five- year survival rates were 86%, 50% and 38% respectively for patients treated with epoprostenol compared with 40%, 40% and 8% survival rates at idetical periods for patients treated conventionally (p = 0,02). Functional class and the mean distance walked in the 6 minutes test were improved in patients treated with prostacyclin (p < 0,01). Serious complications attributable to the delivery system included 3 deaths, mainly due to infection. CONCLUSION: Continuous intravenous epoprostenol therapy improves survival and exercise capacity in patients with severe pulmonary arterial hypertension despite potentially serious complications attributable to the delivery system.

Guía de diagnóstico y tratamiento de la hipertensión pulmonar: resumen de recomendaciones / Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Summary of Recommendations

La hipertensión pulmonar es un trastorno hemodinámico definido por el aumento anómalo de la presión arterial pulmonar, que puede presentarse en numerosas enfermedades y situaciones clínicas. Las causas de hipertensión pulmonar se clasifican en 5 grandes grupos: arterial, debida a cardiopatía izquierda, debida a enfermedad pulmonar y/o hipoxemia, tromboembólica crónica y de mecanismo no establecido y/o multifactorial. El presente documento expone de forma resumida las recomendaciones de la Guía de Diagnóstico y Tratamiento de la Hipertensión Pulmonar de la Sociedad Española de Neumología y Cirugía Torácica. En dicha guía se presentan las pautas actuales de diagnóstico y tratamiento de los distintos grupos de hipertensión pulmonar

Pulmonary hypertension is a hemodynamic disorder defined by abnormally high pulmonary artery pressure that can occur in numerous diseases and clinical situations. The causes of pulmonary hypertension are classified into 5 major groups: arterial, due to left heart disease, due to lung disease and/or hypoxemia, chronic thromboembolic, with unclear and/or multifactorial mechanisms. This is a brief summary of the Guidelines on the Diagnostic and Treatment of Pulmonary Hypertension of the Spanish Society of Pulmonology and Thoracic Surgery. These guidelines describe the current recommendations for the diagnosis and treatment of the different pulmonary hypertension groups