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Chronic thromboembolic pulmonary hypertension (CTEPH) is considered a complication of pulmonary embolism (PE). However, signs of CTEPH may exist in patients with a first symptomatic PE.Which radiologic findings on computed tomography pulmonary angiography (CTPA) at the time of acute PE could indicate the presence of a pre-existing CTEPH?We included unselected patients with acute PE who were prospectively followed for 2 years with a structured visit schedule. Two expert radiologists independently assessed patients' baseline CTPAs for pre-existing CTEPH; in case of disagreement, a decision was reached by 2:1 majority with a third expert. In addition, the radiologists checked for predefined individual parameters suggesting chronic PE and pulmonary hypertension. Signs of chronic PE or CTEPH at baseline were identified in 46 (15%) of 303 included patients. Intravascular webs, arterial narrowing or retraction, dilated bronchial arteries and right ventricular hypertrophy were the main drivers of the assessment. Five (1.7%) patients were diagnosed with CTEPH during follow-up. All four patients diagnosed with CTEPH early (83-108 days after acute PE) could be found in enriched subgroups based on the experts' overall assessment or fulfilling a minimum number of the predefined radiologic criteria at baseline. The specificity of pre-existing CTEPH diagnosis and the level of radiologists' agreement improved as the number of required criteria increased.Searching for predefined radiologic parameters suggesting pre-existing CTEPH at the time of acute PE diagnosis may allow for targeted follow-up strategies and risk-adapted CTEPH screening, thus facilitating earlier CTEPH diagnosis.

BACKGROUND: To evaluate whether volumetric iodine quantification of the lung allows for the automatic identification of patients with chronic thromboembolic pulmonary hypertension (CTEPH) and whether the extent of pulmonary malperfusion correlates with invasive hemodynamic parameters. METHODS: Retrospective data base search identified 30 consecutive patients with CTEPH who underwent CT pulmonary angiography (CTPA) on a spectral-detector CT scanner. Thirty consecutive patients who underwent an identical CT examination for evaluation of suspected acute pulmonary embolism and had no signs of pulmonary embolism or PH, served as control cohort. Lungs were automatically segmented for all patients and normal and malperfused volumes were segmented based on iodine density thresholds. Results were compared between groups. For correlation analysis between the extent of malperfused volume and mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) 3 patients were excluded because of a time span of more than 30 days between CTPA and right heart catheterization. RESULTS: Patients with CTEPH had a higher percentage of malperfused lung compared to controls (43.25%±24.72% vs. 21.82%±20.72%; P=0.001) and showed reduced mean iodine density in malperfused and normal-perfused lung areas, as well as in the vessel volume. Controls showed a left-tailed distribution of iodine density in malperfused lung areas while patients with CTEPH had a more symmetrical distribution (Skew: –0.382±0.435 vs. –0.010±0.396; P=0.004). Patients with CTEPH showed a significant correlation between the percentage of malperfused lung volume and the PVR (r=0.57, P=0.001). CONCLUSIONS: Volumetric iodine quantification helps to identify patients with CTEPH by showing increased areas of malperfusion. The extent of malperfusion might provide a measurement for disease severity in patients with CTEPH.

Background Pulmonary arterial hypertension (PAH) is a progressive disease with limited survival. Iron deficiency (ID) correlates with disease severity and mortality. While oral iron supplementation was shown to be insufficient in such patients, the potential impact of parenteral iron on clinical measures warrants further investigation. Methods We retrospectively analysed the long‐term effects of intravenous ferric carboxymaltose (FCM) on iron status and clinical measures in patients with PAH and ID [ferritin

BACKGROUND Few data are available on the long-term course and predictors of quality of life (QoL) following acute pulmonary embolism (PE). RESEARCH QUESTION What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months following an acute PE? STUDY DESIGN AND METHODS The Follow-up after Acute Pulmonary Embolism (FOCUS) study prospectively followed up consecutive adult patients with objectively diagnosed PE. Patients were considered for study who completed the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire at predefined visits 3 and 12 months following PE. The course of disease-specific QoL as assessed using the PEmb-QoL and the impact of baseline characteristics using multivariable mixed effects linear regression were studied; also assessed was the course of generic QoL as evaluated by using the EuroQoL Group 5-Dimension 5-Level utility index and the EuroQoL Visual Analog Scale. RESULTS In 620 patients (44% women; median age, 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease in the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI, -3.2 to -5.5). Female sex, cardiopulmonary disease, and higher BMI were associated with worse QoL at both 3 and 12 months. Over time, the association with BMI became weaker, whereas older age and previous VTE were associated with worsening QoL. Generic QoL also improved: the mean ± SD EuroQoL Group 5-Dimension 5-Level utility index increased from 0.85 ± 0.22 to 0.87 ± 0.20 and the visual analog scale from 72.9 ± 18.8 to 74.4 ± 19.1. INTERPRETATION In a large cohort of survivors of acute PE, the change of QoL was quantified between months 3 and 12 following diagnosis, and factors independently associated with lower QoL and slower recovery of QoL were identified. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management. CLINICAL TRIAL REGISTRATION German Clinical Trials Registry (Deutsches Register Klinischer Studien: www.drks.de); No.: DRKS00005939.

Pulmonary hypertension (PH) is a frequent hemodynamic condition that is highly prevalent in patients with heart failure and reduced (HFrEF) or preserved ejection fraction (HFpEF). Irrespective of left ventricular EF, the presence of PH and right ventricular (RV) dysfunction are highly relevant for morbidity and mortality in patients with heart failure. While elevated left-sided filling pressures and functional mitral regurgitation primarily lead to post-capillary PH, current guidelines and recommendations distinguish between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH), the latter being defined by a pulmonary vascular resistance (PVR) of ≥3 Wood units. Here, we describe the pathophysiology and clinical relevance of these distinct entities, and report on the diagnostic work-up including remote pulmonary artery pressure (PAP) monitoring. Furthermore, we highlight strategies to manage PH and improve RV function in heart failure, which may include optimized management of HFrEF and HFpEF (medical and interventional), sufficient volume control, catheter-based mitral valve repair, and-in selected cases-targeted PH therapy. In this context, we also highlight gaps in evidence and the need for further research.

Pulmonary hypertension (PH) is an important contributor to morbidity and mortality in patients with left-sided heart disease, including valvular heart disease. In this context, elevated left atrial pressure primarily leads to the development of post-capillary PH. Despite the fact that repair of left-sided valvular heart disease by surgical or interventional approaches will improve PH, recent studies have highlighted that PH (pre- or post-interventional) remains an important predictor of long-term outcome. Here, we review the current knowledge on PH in valvular heart disease taking into account new hemodynamic PH definitions, and the distinction between post- and pre-capillary components of PH. A specific focus is on the precise characterization of hemodynamics and cardiopulmonary interaction, and on potential strategies for the management of residual PH after mitral or aortic valve interventions. In addition, we highlight the clinical significance of tricuspid regurgitation, which may occur as a primary condition or as a consequence of PH and right heart dilatation (functional). In this context, proper patient selection for potential tricuspid valve interventions is crucial. Finally, the article highlights gaps in evidence, and points toward future perspectives.

To evaluate the value of spectral-detector CT (SDCT) in the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), its differentiation against other etiologies of pulmonary hypertension (PH) and in the prediction of disease severity.60 patients with suspected PH underwent SDCT. Additional diagnostic tests in accordance with the ESC guidelines including right heart catherization and VQ-SPECT were performed. After full diagnostic work-up patients were classified as: 21 precapillary PH, 5 postcapillary PH, 6 combined pre- and postcapillary PH, 19 CTEPH, 9 no PH. SDCT examinations were analyzed by two blinded readers deciding on the diagnosis of CTEPH and scoring the extent of perfusion abnormalities on iodine density images. An additional reading was performed using conventional CTPA images only.With access to SDCT data, both readers reached a sensitivity of 100% for the diagnosis of CTEPH with a specificity of 95.1% and 87.8%. On analysis of conventional CTPA images alone, specificity and diagnostic confidence decreased for both readers (Specificity 90.2 and 85.3%) while sensitivity dropped for the less experienced reader only (Sensitivity 78.9%). Patients with PH showed significantly more perfusion abnormalities than patients without PH (16.6 ± 8.4 vs. 9.5 ± 8.9 p 0.001) and the extent of perfusion abnormalities correlated with the mean pulmonary artery pressure (r = 0.37 p = 0.008).SDCT offers confident identification of patients with CTEPH and enables a comprehensive analysis of pulmonary vasculature, pulmonary perfusion and the lung parenchyma in a single examination for patients with suspected PH.

Heart failure with preserved ejection fraction (HFpEF) is frequently associated with pulmonary hypertension (PH), which substantially impacts survival. Based on pulmonary vascular resistance (PVR) and the diastolic pressure gradient (DPG), current guidelines distinguish between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH). However, the therapeutic consequences of this sub-classification remain entirely unclear. We specifically investigated the efficacy and safety of PDE5i in patients with HFpEF and CpcPH.In 40 hemodynamically precisely characterized patients with HFpEF and Cpc-PH who were treated with a PDE5i for at least 12 months, the therapeutic effect on 6-minute walk distance (6MWD), WHO functional class (FC), NTproBNP levels, right ventricular function, and hospitalization rates was evaluated.Patients' mean age was 73 ± 9 years, and comorbidities were frequent (78% hypertension, 58% atrial fibrillation, 35% diabetes). Initially, 38 patients (95%) were in WHO-FC III and 2 patients (5%) in WHO-FC II. Prior to PDE5i initiation, mean PAPm was 46.2 ± 10.3 mmHg, PAWP 21.2 ± 4.7 mmHg, DPG 5.5 ± 7.2 mmHg, and PVR 6.2 ± 3.0 WU. After 12 months of PDE5i therapy, the 6MWD increased from initially 277 ± 17 to 340 ± 18 m (p 0.001), and the proportion of patients in WHO-FC I/II increased from 5% to 37.5%. NTproBNP levels decreased by 33% (p = 0.004), and TAPSE improved from 16.8 ± 0.7 mm at baseline to 18.2 ± 0.6 mm (p = 0.01). The rate of HF-associated hospitalizations was substantially lower in the 12 months post PDE5i initiation compared to the prior 12 months. The DPG had no impact on the response to therapy. No deaths occurred, and typical side effects of PDE5i were observed.These data indicate that at least a subset of precisely characterized patients with HFpEF and CpcPH who tolerate PDE5i may benefit from targeted therapy. A randomized study in this particular sub-population is warranted.

Atrial septal defect (ASD) is one of the most frequent congenital heart diseases (CHD). Up to 10% of adults with an ASD develop pulmonary arterial hypertension (PAH, PAH-CHD) in their lifetime. Despite improved therapy options, gravidity remains a substantial risk for both maternal and neonatal mortality in PAH-CHD patients. In our patient, gravidity remained uncomplicated until week 32, under specific monotherapy with tadalafil, before onset of dyspnea and markedly increase of systolic pulmonary arterial pressure (PAP) was observed in echocardiography. Urgent Caesarian delivery was performed without any complications and a healthy baby was born. However, immediately afterwards, the patient desaturated (SpO2 65%, PaO 2 37 mmHg) due to a shunt inversion with now right-to-left shunt through the residual ASD. She was admitted to our intensive care unit and specific PH therapy was escalated to a triple combination of tadalafil, ambrisentan, and iloprost. Hereafter, in a slow process of approximately three weeks, the patient's condition improved to baseline. This rare case of a young woman with high-risk pregnancy in PAH-CHD highlights the hemodynamic changes and treatment options during pregnancy in these patients and emphasizes the urgency of a close monitoring at specialized GUCH/PAH centers with experience in managing PAH under these circumstances.

In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines aiming at their practical implementation, considering country-specific issues, and including new evidence, where available. To this end, a number of working groups was initiated, one of which was specifically dedicated to general measures (i.e. physical activity/supervised rehabilitation, pregnancy/contraception, elective surgery, infection prevention, psychological support, travel) and supportive therapy (i.e. anticoagulants, diuretics, oxygen, cardiovascular medications, anaemia/iron deficiency, arrhythmias) for PAH. While the European guidelines provide detailed recommendations for the use of targeted PAH therapies as well as supportive care, detailed treatment decisions in routine clinical care may be challenging, and the relevance of supportive care is often not sufficiently considered. In addition, new evidence became available, thus requiring a thorough reevaluation of specific recommendations. The detailed results and recommendations of the working group on general measures and supportive therapy for PAH, which were last updated in the spring of 2018, are summarized in this article.

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. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

Background Few data are available on the long-term course and predictors of quality of life (QoL) after acute pulmonary embolism (PE). Aims To evaluate the kinetics and determinants of QoL at 3 and 12 months after acute PE. Methods The Follow-Up after acute pulmonary embolism (FOCUS) study prospectively followed consecutive adult patients with objectively diagnosed PE. For this analysis, we considered patients who completed the Pulmonary Embolism QoL (PEmb-QoL) Questionnaire at two predefined visits 3 and 12 months after PE. PEmb-QoL, studied as total score and in its six dimensions, ranges from 0% (best QoL) to 100% (worst QoL). We studied the course of PEmb-QoL and the impact of baseline characteristics using multivariable linear regression. Results In 617 included patients (44% women, median age 62 years), overall QoL improved from 3 to 12 months, with a decrease of the mean PEmb-QoL score from 25.3% to 21.5% (p-value Conclusions In a large cohort of patients with pulmonary embolism, we quantified the improvement of QoL between 3 and 12 months after diagnosis. We identified factors independently associated with lower QoL and slower recovery of QoL that may reflect special patient needs. These estimates may facilitate the planning and interpretation of clinical trials with QoL as a study outcome. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): University Medical Center of the Johannes Gutenberg University, Mainz, Germany; German Federal Ministry of Education and Research

Purpose of review Pulmonary hypertension is a common phenomenon in heart failure patients that is highly relevant for morbidity and outcome. Although postcapillary in nature, the pathophysiology of pulmonary hypertension in patients with heart failure with reduced or preserved ejection fraction is complex, and decisions about management strategies remain challenging. Recent findings Recently, the hemodynamic definitions and subclassification of postcapillary pulmonary hypertension have been revisited. The distinction between isolated postcapillary pulmonary hypertension (IpcPH) and combined post and precapillary pulmonary hypertension (CpcPH) and their definition are essential. Novel data on the prognostic impact of hemodynamic variables and right ventricular function highlight the importance of cardiopulmonary interaction in patients with left-sided heart failure (LHF). Furthermore, the impact of management strategies including medical therapy, remote hemodynamic monitoring, and interventional approaches on hemodynamics and outcome has recently been investigated. Here, we critically review recent developments and future considerations in this field, and highlight distinct treatment strategies targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function. Summary Detailed hemodynamic characterization and proper phenotyping are essential for prognostication and the management of patients with pulmonary hypertension associated with LHF, both in clinical practice and when addressing research questions.

Implantable infusion pumps might improve the convenience and safety of intravenous treprostinil for pulmonary arterial hypertension. The LENUS Pro (R) pump (approved in Europe) has a fixed flow rate. Based on 126 pumps and 2853 refills, we retrospectively analyzed the actual flow rate from 09/2010 to 09/2018. A relevant flow rate variance is evident after three years; therefore, flow rate monitoring and dose adjustment are mandatory.

Summary Background Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH. Methods We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18–75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT02234141 . Findings Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm5. Change in pulmonary vascular resistance was 6·0 dyn·s/cm5 (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm5 (n=35; p=0·21 vs placebo) for 2 mg selonsertib, −28·0 (30·2) dyn·s/cm5 (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and −21·0 (37·9) dyn·s/cm5 (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo. Interpretation Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1–p38 pathway in PAH is warranted. Funding Gilead Sciences.

In patients with pulmonary arterial hypertension (PAH) in addition to targeted medication, supportive training programs may be beneficial. In this pilot study, we evaluated the feasibility, effectiveness, and safety of oscillatory whole-body vibration (WBV) in patients on stable targeted therapy. We randomized 22 patients with PAH (PAP ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg) in WHO functional class II or III to receive training (16 sessions of 1 h within 4 weeks) or to a control group that subsequently received WBV. Follow-up measures included 6-minute walking, cardiopulmonary exercise test, echocardiography, N-terminal prohormone of brain natriuretic peptide (NTproBNP), and functional analytic parameters (“chair-rising” and “two-leg jump” test) as well as health-related quality of life (HRQoL; SF-36, LH-PH questionnaires). Patients who underwent WBV showed a significant improvement of 39.7 ± 7.8 m in 6-min walking distance (6MWD) (p < 0.05; WBV +35.4 ± 10.9 m, control group −4.4 ± 7.6 m). Taken together, all patients (n = 22) showed significant net improvements versus baseline in the 6MWD (+38.6 m), peakVO2 (+65.7 mL/min), anaerobic threshold (+40.9 mL VO2/min), muscle power (+4.4%), and HRQoL (SF-36 + 9.7, LPH −11.5 points) (all p < 0.05). WBV was well tolerated in all patients. With this concept of “passive” training, WBV can improve exercise capacity and quality of life even in physically very limited patients substantially.

BACKGROUND We examined safety and long-term outcomes of intravenous treprostinil administered via the implantable LENUS Pro pump in patients with severe pulmonary hypertension (PH). METHODS Patients with PH undergoing pump implantation between December 2009 and October 2016 in German referral centers were retrospectively analyzed (end of follow-up: May 2017). The primary objective was to determine long-term safety of the implantable pump. Secondary end points were 3-year survival and prognostic relevance of pre-implantation hemodynamics. RESULTS We monitored 129 patients (120 with pulmonary arterial hypertension, 1 with PH due to lung diseases, and 8 with inoperable chronic thromboembolic PH) for 260 patient-years (median follow-up, 19 months; interquartile range, 11–34 months). There were 82 complications/peri-procedural events in 60 patients; of these, 57 were serious adverse events (0.60 per 1,000 treatment-days), including 2 periprocedural deaths due to right heart failure. The incidence of complications related to the pump, catheter, infection, and pump pocket per 1,000 treatment-days was 0.074, 0.264, 0.032 (3 local infections; no bloodstream infections), and 0.380, respectively. Three-year overall and transplant-free survival were 66.5% and 55.7%, respectively (39 patients died; 16 underwent lung transplantation). Baseline cardiac index independently predicted transplant-free survival (multivariate hazard ratio, 1.90; 95% confidence interval, 1.11–3.28; p = 0.019; n = 95). CONCLUSIONS Our data suggest that intravenous treprostinil via the LENUS Pro pump in advanced PH is associated with a very low risk of bloodstream infections, but other serious adverse events may occur. Therefore, this therapy needs standardization and should be offered in specialized PH centers only. Further technical advances of the pump system and prospective studies are needed.

BACKGROUND 4D flow imaging can be used to evaluate vortex formation in the pulmonary artery seen in patients with pulmonary hypertension. We evaluated if a k-t accelerated multi-VENC (velocity encoding) 4D flow acquisition improves image quality, inter-reader agreement and correlation with hemodynamic parameters. METHODS A total of 14 patients with pulmonary hypertension (5 females, 9 males; mean age 61 ± 16 years) underwent 4D flow MRI (magnetic resonance imaging) and right heart catheterization. In addition to that, 13 healthy volunteers (2 females, 11 males, mean age 33 ± 12 years) also underwent 4D flow MRI. Multi- and single-VENC datasets were reconstructed and evaluated for vortex formation and vortex duration by two blinded readers and image quality was rated on a 5-point scale. RESULTS Both readers rated image quality as significantly higher on multi-VENC datasets (3.96 ± 0.71 vs. 2.56 ± 0.93, p

Objective To evaluate the influence of monoenergetic reconstructions using a spectral detector CT (SDCT) on the computer aided detection (CAD) of pulmonary artery embolism (PAE) on CT pulmonary angiography (CTPA) and CT in venous contrast phase (CTV). Material and Methods A retrospective data base search identified 15 patients with CTPA and 18 patients with CTV and diagnosis of PAE. For these patients, monoenergetic (monoE) images at different energy levels or with a fixed attenuation in the pulmonary artery were generated and independently analyzed using a commercially available computer aided detection (CAD) tool. Attenuation in the pulmonary artery and in the embolus was measured. Results For CTPA and CTV, in monoenergetic images the difference in attenuation between vessel and embolus was significantly higher than in conventional images. In CTPA the detection rate was highest in the >500 HU monoE images with 67,9% detected emboli and 93,3% of patients correctly identified as having PAE. At the same time the false positive rate could be significantly reduced by using monoE images compared to conventional images. Detection rates for CTV were lower than in CTPA but were raised significantly by monoE reconstructions. Conclusions The combination of SDCT and CAD improves the diagnostic accuracy of CAD and enables CAD interpretation of CTV.

Objective In patients with pulmonary arterial hypertension (PAH), supportive therapies may be beneficial in addition to targeted medical treatment. Here, we evaluated the effectiveness and safety of oscillatory whole-body vibration (WBV) in patients on stable PAH therapy. Methods Twenty-two patients with PAH (mean PAP≥25 mm Hg and pulmonary arterial wedge pressure (PAWP)≤15 mm Hg) who were in world health organization (WHO)-Functional Class II or III and on stable PAH therapy for≥3 months, were randomised to receive WBV (16 sessions of 1-hour duration within 4 weeks) or to a control group, that subsequently received WBV. Follow-up measures included the 6-min walking distance (6MWD), cardiopulmonary exercise testing (CPET), echocardiography, muscle-power, and health-related quality of life (HRQoL; SF-36 and LPH questionnaires). Results When compared to the control group, patients receiving WBV exhibited a significant improvement in the primary endpoint, the 6MWD (+35.4±10.9 vs −4.4±7.6 m), resulting in a net benefit of 39.7±7.8 m (p=0.004). WBV was also associated with substantial improvements in CPET variables, muscle power, and HRQoL. The combined analysis of all patients (n=22) indicated significant net improvements versus baseline in the 6MWD (+38.6 m), peakVO2 (+65.7 mL/min), anaerobic threshold (+40.9 mL VO2/min), muscle power (+4.4%), and HRQoL (SF-36 +9.7, LPH −11.5 points) (all p

Background The implantation of left ventricular assist devices (LVAD) has established its role in therapy for patients with end stage heart failure. Benefits in survival as well as an improved quality of life, compared to optimized medical therapy (OMT) alone, has been proven. There are limited data in the literature on the metabolic changes during exercise in LVAD patients, and in most studies no increase in peak oxygen consumption on cardiopulmonary exercise test (CPET) could be shown early after surgery. However, recent data suggests an improvement in peak oxygen uptake (VO2) as a late effect after rehabilitation. To further investigate these findings we sought to analyse CPET data from patients before LVAD implantation as well as in the early and late follow up in correlation with hemodynamic changes at these times. Methods We collected and retrospectively analysed data of heart failure patients who had undergone LVAD implantation, and in whom a right heart catheterization, a cardiopulmonary exercise test and an echocardiography had been performed at time before, as well as 6 Months and 12 months after LVAD implantation, respectively. Results Data of 43 patients implanted with an LVAD between 2011 and 2017 were analysed. There was significant improvement in cardiac output (3,2 vs 4,3 L/min, p 12 months after LVAD implantation there were no further significant changes in cardiac output, intracardiac pressures or VE/VCO2 slope, which all remained similar to the 6 months follow up. However, at that point, a significant increase in peak VO2 was seen, compared to baseline (1060 vs 1410ml/min, p=0,001) and to 6 months after surgery (Figure 1). Conclusion Cardiac output increases in heart failure patients early after LVAD implantation. Consequently, permanent ventricular off loading results in the reduction of intracardiac pressures and improvement in the VE/VCO2 slope 6 months after surgery. However, a significant rise in peak oxygen consumption could only be noted 12 months after surgery, suggesting either a delayed long-term effect of improved hemodynamics or other causes such as enhanced mobility or training due to improved quality of life.

Background Patients with chronic left and right heart failure show a reduction in peak oxygen uptake (VO2), even with optimal medical therapy. A non-invasive determination whether the mechanism of exercise limitation is primarily due to left or right-heart failure may be a challenge in clinical practice. The simultaneous analysis of metabolic and hemodynamic responses during exercise may allow an improved differentiation of exercise limitation. However, only little is known about the combined hemodynamic/metabolic exercise response patterns in these patients. OBJECTIVES We sought to characterize the simultaneous hemodynamic and metabolic response to exercise in stable patients with chronic, isolated left vs right heart failure. Methods We analyzed a cohort of highly selected patients with isolated right heart failure (group 1) and isolated left heart failure (group 2). All patients were in functional class II and III, and under stable medical Treatment. All patients had received right heart catheterization before enrollment. All of the patients in group 1 and none of the patients in group 2 showed an elevated pulmonary vascular resistance (PVR). All patients received a cardiopulmonary exercise test (CPET) with a ramp protocol up to maximal exercise tolerance. During a second visit, a combined CPET/stress echocardiography was performed with a two step constant work rate protocol. For step 1, a workrate below the patients' anaerobic threshold was chosen. For step 2, 80% of the patients' maximum workrate from the ramp test was chosen. Each step was performed until a complete echocardiographic image acquisition was obtained. Echocardiographic parameters, including stroke volume measurements, were obtained once at rest and for each of the two exercise steps. Results We recruited 18 patients (n=9 in group 1, n=9 in group 2). There were no significant differences in demographic baseline characteristics. There were no adverse events. In the inital ramp CPET, both groups showed a moderate reduction in peak VO2 (53,0±12,4 vs 63,3±12,8% of predicted). The absolute peak VO2 values, corrected for body weight, showed no significant difference (16,7±4,5 vs 16,5±5,1 ml/min/kg). While the increase in VO2 (Figure 1A) and cardiac index (Figure 1B) during step 1 and step 2 of the simultaneous CPET/stress echocardiography was similar between both groups, the increase of stroke volume index with exercise was significantly reduced in the group with right heart failure, while the group with left heart failure increased stroke volume index during exercise (Figure 1C). Figure 1 Conclusions The simultaneous evaluation of hemodynamic and metabolic parameters by CPET/stress echocardiography is safe and may reveal characteristic response patterns to exercise in patients with chronic left vs right heart failure. Patients with right heart failure seem to be less able to increase stroke volume during exercise than patients with left heart failure. Acknowledgement/Funding This project was partly funded by Actelion Pharmaceuticals

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH), but also other significant subgroups of pulmonary hypertension (PH). In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). In every patient with PH of unknown cause CTEPH should be excluded. The primary treatment option is surgical pulmonary endarterectomy (PEA) in a specialized multidisciplinary CTEPH center. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. For balloon pulmonary angioplasty (BPA), there is currently only limited experience. This option - as PEA - is reserved to specialized centers with expertise for this treatment method. In addition, a brief overview is given on pulmonary artery sarcoma, since its surgical treatment is often analogous to PEA. The recommendations of this working group are summarized in the present paper.

Acute pulmonary embolism (PE) is a frequent cause of death and serious disability. The risk of PE-associated mortality and morbidity extends far beyond the acute phase of the disease. In earlier follow-up studies, as many as 30 % of the patients died during a follow-up period of up to 3 years, and up to 50 % of patients continued to complain of dyspnea and/or poor physical performance 6 months to 3 years after the index event. The most feared ‘late sequela’ of PE is chronic thromboembolic pulmonary hypertension (CTEPH), the true incidence of which remains obscure due to the large margin of error in the rates reported by mostly small, single-center studies. Moreover, the functional and hemodynamic changes corresponding to early, possibly reversible stages of CTEPH, have not been systematically investigated. The ongoing Follow-Up after acute pulmonary embolism (FOCUS) study will prospectively enroll and systematically follow, over a 2-year period and with a standardized comprehensive program of clinical, echocardiographic, functional and laboratory testing, a large multicenter prospective cohort of 1000 unselected patients (all-comers) with acute symptomatic PE. FOCUS will possess adequate power to provide answers to relevant remaining questions regarding the patients’ long-term morbidity and mortality, and the temporal pattern of post-PE abnormalities. It will hopefully provide evidence for future guideline recommendations regarding the selection of patients for long-term follow-up after PE, the modalities which this follow-up should include, and the findings that should be interpreted as indicating progressive functional and hemodynamic post-PE impairment, or the development of CTEPH. Electronic supplementary material The online version of this article (doi:10.1007/s11239-016-1415-7) contains supplementary material, which is available to authorized users.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subgroup of pulmonary hypertension that differs from all other forms of PH in terms of its pathophysiology, patient characteristics and treatment. For implementation of the European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension in Germany, the Cologne Consensus Conference 2016 was held and last updated in spring of 2018. One of the working groups was dedicated to CTEPH, practical and controversial issues were commented and updated. In every patient with suspected PH, CTEPH or chronic thromboembolic disease (CTED, i.e. symptomatic residual vasculopathy without pulmonary hypertension) should be excluded. Primary treatment is surgical pulmonary endarterectomy (PEA) in a multidisciplinary CTEPH centre. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. There is increasing experience with balloon pulmonary angioplasty (BPA) for inoperable patients; this option, like PEA, is reserved for specialised centres with expertise in this treatment method.

Background: In pulmonary arterial hypertension (PAH), iron deficiency (ID) correlates with disease severity and mortality. In a pilot study, we showed a short-term benefit of intravenous (i.v.) iron substitution on exercise tolerance and quality of life. Aims and objectives: We now examined the long-term effects of i.v. iron carboxymaltose (ICM) on exercise tolerance and right heart function for a period of 15 months. Methods: 20 patients with PAH and ID (ferritin Results: In patients with ID, a single ICM infusion resulted in a rapid and sustained improvement of iron status at 2 and 15 months (serum iron, ferritin, TSAT, all p Conclusion: ICM was well tolerated in addition to targeted PAH therapy and led to a significant long-term benefit in PAH patients with ID. A controlled study is warranted.

Background Pulmonary arterial hypertension (PAH) is a progressive condition harboring a poor prognosis. Iron deficiency in PAH correlates with disease severity and mortality. While replacement therapy may be beneficial, dietary iron absorption is impaired in PAH patients by hepcidin, a key regulatory protein of iron homoeostasis. We therefore assessed the therapeutic potential and safety of intravenous iron supplementation in patients with PAH and iron deficiency. Methods 20 patients with PAH and iron deficiency, who were on stable targeted PAH therapy, received a single infusion of ≤1000mg ferric carboxymaltose. All patients were assessed at baseline and two months after iron treatment. Exercise capacity was evaluated based on the 6-minute-walking distance (6MWD), and quality of life (QoL) was assessed by the SF-36 questionnaire (100 point scale). The effects were compared to 20 matched patients with stable PAH without iron deficiency who did not receive ferric carboxymaltose. Results In iron deficient patients, iron supplementation led to a marked improvement of iron status (serum iron 5.7±0.4 to 11.1±1.1μmol/L, ferritin 29.3±6.3 to 145.2±25.4μg/L, transferrin saturation 7.5±0.7 to 19.3±2.3%, all p ≤0.001). Iron-deficient patients receiving ferric carboxymaltose showed a significant increase of the 6MWD from 346.5±28.3 to 374.0±25.5m ( p =0.007), whereas no significant changes were found in the control group not receiving iron supplementation (6MWD 389.9±25.3 to 379.6±26.2m; n.s.), resulting in a net increase in the 6MWD of 37.8m ( p =0.003). This was associated with an improvement in QoL (SF-36 score from 44.3±3.7 to 50.6±3.6; p =0.01). Only minimal side-effects were reported. Conclusions These data indicate that parenteral iron supplementation with ferric carboxymaltose significantly improves exercise capacity and QoL and is well tolerated in patients with PAH and iron deficiency, and when administered in addition to targeted PAH therapies. Our results provide proof of concept for further studies evaluating the potential of iron as an adjunct in PAH treatment on a larger scale.

Background: Subcutaneous treprostinil has dose-dependent beneficial effects in patients with severe pulmonary arterial hypertension, but adverse effects like infusion site pain can lead to treatment discontinuation. Objectives: The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of subcutaneous treprostinil using proactive infusion site pain management. Methods: Effects of rapid up-titration dosing regimen on tolerability and clinical parameters were evaluated in this 16-week, open-label multi-centre study. Results: Thirty-nine patients with idiopathic or heritable pulmonary arterial hypertension on stable treatment with oral pulmonary arterial hypertension-approved drugs (90% on dual combination therapy) were included. Patients achieved a median treprostinil dosage of 35.7 ng/kg/min after 16 weeks. A good overall safety profile was demonstrated with 3 patients (8%) withdrawing due to infusion site pain, which occurred in 97% of patients. After 16 weeks, median 6-min walking distance, cardiac index, pulmonary vascular resistance, and tricuspid annular plane systolic excursion improved. Conclusions: Rapid up-titration of subcutaneous treprostinil was well tolerated, achieving a clinically effective dose associated with improvement of exercise capacity and haemodynamics after 16 weeks. A rapid dose titration regimen and proactive infusion site pain management may improve the handling of this therapy and contribute to better treatment outcome.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease. For patients with operable CTEPH, there is a clear recommendation for surgical removal of persistent thrombi by pulmonary endarterectomy (PEA). However, without the presence of PH, therapeutic management of chronic thromboembolic disease (CTED) is challenging - especially in highly trained subjects exceeding predicted values of maximal exercise capacity. Case presentation A 43-year-old male athlete reported with progressive exercise limitation since 8 months. Six months earlier, pulmonary embolism had occurred, and was treated since with oral anticoagulation. A pulmonary ventilation/perfusion scan showed severe ventilation/perfusion mismatch: chest CT and pulmonary angiography revealed bilateral wall-adherent thrombotic material, but pulmonary hemodynamics were completely normal. His peak oxygen uptake exceeded predicted values, however exercise ventilatory efficiency was abnormal, compared to a matching athlete. After thoroughly discussing therapeutic options with the patient, he successfully underwent pulmonary endarterectomy at an expert center. Five and twelve months after surgery, his maximal exercise capacity and ventilatory efficiency profoundly improved beyond preoperative values, and his subjective exercise tolerance had returned to normal. Conclusions Significant CTED may be present without relevant pathologic changes in pulmonary hemodynamics at rest. Reaching normal values of maximal exercise capacity does not exclude pulmonary vascular disease in highly trained subjects. More data are needed to evaluate the risk-/benefit ratio of PEA in patients with CTED and normal pulmonary hemodynamics. A thorough discussion with the patient as well as shared decision making regarding therapy are mandatory. Cardiopulmonary exercise testing may add important clinical information in the non-invasive diagnostic evaluation at baseline and during follow-up.

Anamnese und klinischer Befund: Eine 70-jahrige Patientin wurde mit progredienter Dyspnoe, akuter Gewichtszunahme und peripheren Beinodemen bei einer vorbekannten Myokardhypertrophie, diastolischer Dysfunktion und begleitender, schwerer pulmonaler Hypertonie (PH) vorstellig. Untersuchungen: Die korperliche Untersuchung zeigte Zeichen der kardialen Dekompensation. Echokardiographisch waren neben einer Myokardhypertrophie, einem vergroserten linken Atrium und vergroserten rechten Herzabschnitten ein ausgepragter Druckgradient uber der Trikuspidalklappe sichtbar. Die invasiv gemessene Hamodynamik des kleinen Kreislaufs zeigte eine deutliche Druck- und Widerstandserhohung in der pulmonalen Zirkulation, die mit einem erhohten pulmonal arteriellen Verschlussdruck (PAWP) und einem ausgepragten transpulmonalen Gradienten (TPG) einherging. Diagnose, Therapie und Verlauf: In Zusammenschau der Befunde wurde eine postkapillare PH mit einer ausgepragten prakapillaren Komponente bei kardialer Dekompensation diagnostiziert. Bei Zeichen einer relevanten Volumenuberladung wurde eine forcierte Diurese eingeleitet. Rasch konnte die Patientin rekompensiert werden, verlor innerhalb von 5 Tagen insgesamt 7 kg an Gewicht und fuhlte sich klinisch deutlich besser. In einer erneuten invasiven Untersuchung war der pulmonal arterielle Druck nahezu auf Normwerte gesunken, und die zuvor diagnostizierte prakapillare Komponente war nicht mehr nachweisbar. Folgerungen: Die PH ist ein haufiges Phanomen bei systolischer und diastolischer Herzinsuffizienz. Sie kann hamodynamisch zunachst als Mischform mit einer pra- und postkapillaren Komponente imponieren. Der Volumenstatus beeinflusst die Hamodynamik in erheblichem Mase. Eine adaquate Therapie der Herzinsuffizienz, insbesondere eine ausreichende Diurese, kann die pulmonale Hamodynamik gunstig beeinflussen. Daher sollte eine hamodynamische Untersuchung der pulmonalen Zirkulation stets in kompensiertem Zustand erfolgen. Im Umkehrschluss kann jedoch gefolgert werden, dass beim diuretisch vorbehandelten Patienten eine postkapillare PH auch bestehen kann, wenn der gemessene PAWP

Despite novel treatment options to achieve vessel patency after percutaneous coronary interventions, vascular restenosis remains a significant clinical problem (1). Critical events for neointima formation at sites of vascular injury are the attraction of vascular smooth muscle cells (VSMCs) from the media, their neointimal proliferation, and extracellular matrix deposition (1–3). The inhibition of central cell cycle–regulating proteins such as mammalian target of rapamycin is efficient in reducing neointima formation after coronary stenting (4,5). However, this approach is hampered by the burden of in-stent thrombosis, because mammalian target of rapamycin inhibition also restrains the proliferation of endothelial cells and thus attenuates re-endothelialization (6,7). Sophisticated novel therapeutic approaches should selectively target VSMC proliferation and migration without affecting endothelial cell function. Platelet-derived growth factor (PDGF) represents the most potent mitogen and chemoattractant for VSMCs (8,9), whereas it does not elicit significant effects on endothelial cells. Furthermore, PDGF and its beta receptor subtype (βPDGFR), which is abundantly expressed in VSMC (10,11), are significantly upregulated and activated at sites of vascular injury (12,13), making the βPDGFR a promising target for therapeutic interventions. However, recent studies on the role of the βPDGFR for neointima formation yielded conflicting results (14,15). Although inhibition of PDGFR signaling was effective in reducing restenosis formation in animal models, systemic administration of a PDGFR inhibitor failed to prevent the recurrence of in-stent restenosis in humans. Therefore, it appears crucial to more precisely define the role of PDGF for neointima formation and to identify the signaling pathways by which the βPDGFR mediates cellular responses that contribute to vascular disease. We used a genetic approach to address 3 important questions: 1) what are the signaling pathways that mediate PDGF-dependent migration and proliferation in VSMCs; 2) is βPDGFR signaling really critical for neointima formation in vivo; and 3) can the disruption of specific signaling pathways prevent neointima formation? Upon ligand binding, the βPDGFR recruits and activates several SH2 domain-containing signaling molecules that each stably associate with the receptor at phosphorylated tyrosine residues that serve as specific docking sites (16). These include Src family kinases (Src), phosphatidylinositol 3-kinase (PI3K), the GTPase-activating protein of Ras (RasGAP), SHP-2, and phospholipase Cγ1 (PLCγ). To systematically investigate the role of each individual signaling pathway, we used a series of chimeric colony-stimulating factor-1 receptor (CSF1R)/βPDGFR mutants in which the tyrosine residues required for binding of each signaling molecule were individually replaced with phenylalanine (17). Using this system, we were able to precisely characterize the signal relay mechanisms that govern PDGF-dependent chemotaxis and cell cycle progression in VSMCs. These studies particularly identified PI3K and PLCγ as critical signaling enzymes in vitro. Consequently, blunting of PDGF-dependent PI3K and PLCγ signaling in F3 mice, which lack the respective binding sites in the βPDGFR (18), dramatically reduced neointima formation after vascular injury in vivo.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations on the diagnosis of pulmonary hypertension (PH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the treatment of pulmonary arterial hypertension (PAH). This commentary describes in detail the results and recommendations of the working group on treatment of PAH which were last updated in October 2011.

Platelet-derived growth factor β-receptor (βPDGFR)-mediated proliferation of vascular smooth muscle cells (VSMC) plays a pivotal role in the development of restenosis. The βPDGFR binds and activates cytoplasmic signaling molecules such as Src, PI 3-kinase (PI3K), RasGAP, SHP-2 and phospholipase C-gamma (PLCγ). However, the βPDGFR-induced signaling pathways leading to cell cycle progression are largely unknown. In order to characterize the signaling molecules, which are important for βPDGFR-induced VSMC proliferation, we generated several stable VSMC lines with mutated βPDGFRs which were unable to bind/activate each individual signaling molecule. BrdU incorporation assays revealed PI3K and PLCγ as the main mediators of βPDGFR-mediated VSMC proliferation. Deletion of the binding sites for PI3K or PLCγ diminished DNA-synthesis about 47 ± 6% and 54 ± 5%, respectively, whereas the deletion of Src, RasGAP, or SHP-2 binding to the βPDGFR had no influence on the mitogenic response. Mutant cell lines which were only able to bind/activate PI3K or PLCγ induced 43 ± 4% and 52 ± 5% of the WT response, respectively. We further investigated the influence of PI3K and PLCγ on the distinct expression of the key players of cell cycle progression. Western blot analysis revealed that βPDGFR-activated PI3K mainly mediated the up-regulation of cyclin D1, whereas activation of PLCγ mediated the down-regulation of the cyclin-dependent kinase-inhibitor p27 kip1 . Consistently, βPDGFR-dependent phosphorylation of the retinoblastoma protein which is important for the G1/S transition was attenuated when either the binding of PI3K or PLCγ to the βPDGFR was abolished. Moreover, we confirmed our in vitro results in an in vivo model of balloon-induced carotid artery neointima formation. Mice lacking binding of PI3K and PLCγ to the βPDGFR (F3 mice) developed ~50% less neointima formation after balloon angioplasty compared to control WT mice after 3 weeks (p < 0.05). These results indicate that the mitogenic signal of the β PDGFR is mediated by PI3K and PLCγ affecting distinct targets of cell cycle progression. Targeting specific downstream molecules of the βPDGFR in VSMCs might provide a novel approach to reduce neointima formation in patients undergoing balloon angioplasty.

Background: Pulmonary arterial hypertension (PAH) is a gradually worsening disease with an unfavourable outcome. Iron deficiency seemingly has an essential part in the progress of the disease, as its relationship with disease severity and mortality from any cause has been demonstrated. While suitable substitution therapy may be advantageous (analogous to patients with left heart failure), iron absorption from the gut is suppressed in PAH by hepcidin, the master regulator of iron metabolism. We therefore examined the potential benefit of intravenous iron administration in iron deficient PAH patients. Methods: A single infusion of ≤ 1000 mg ferric carboxymaltose was administered to 20 iron deficient patients with PAH (NYHA-FC II/III) on stable background PAH treatment. These patients were assessed at baseline and two months after intervention. The 6-minute-walking distance (6MWD) was measured to assess exercise capacity and the SF-36 questionnaire (100 point scale) was used to evaluate quality of life. The results were compared with 20 matched patients with stable disease who were not given iron infusions. Results: In patients with iron deficiency, iron infusion led to a markedly enhanced iron status (serum iron 5.7±2.0 to 11.1±5.0 μmol/l, ferritin 29.3±28.2 to 145.2±113.7 μg/dl, transferrin saturation 7.5±3.1 to 19.3±10.2%, all p