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Giovanbattista Ippoliti,1,2 Andrea Maria D'Armini,2 Marco Lucioni,3 Mazen Marjieh,1 Mario Viganò21UO Medicina Interna, Policlinico di Monza, Monza, Italy; 2Department of Surgical Sciences, Charles Dubost Transplant Center, Fondazione IRCCS San Matteo Hospital, 3Anatomic Pathology, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, ItalyAbstract: The development of new immunosuppressive drugs for kidney transplantation resulted both in better short-term outcomes and in decreased metabolic, cardiovascular, and nephrotoxicity risk. Belatacept belongs to a new class of immunosuppressive drugs that selectively inhibits T-cell activation by preventing CD28 activation and by binding its ligands B7-1 and B7-2. The result is an inactivation of costimulatory pathways. A comparative analysis of the BENEFIT and BENEFIT-EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A (CsA) regimens: belatacept likewise outperformed CsA in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation. About 20% of belatacept-treated patients developed adverse effects which included anemia, pyrexia, neutropenia, diarrhea, urinary tract infection, headache, and peripheral edema. At present, belatacept does not seem to predispose patients to a higher rate of infection than CsA maintenance immunosuppression. The risk of posttransplant lymphoproliferative diseases was higher in Epstein–Barr virus (EBV)-seronegative patients than in EBV-seropositive patients, but the risk may be reduced by use of a less intensive regimen and avoidance of EBV-negative patients and of patients whose pretransplant EBV serology is unknown. Belatacept provides a new option for immunosuppressive therapy in kidney transplantation, but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status.Keywords: costimulation, organ transplantation, belatacept

The pharmacokinetic properties of immunosuppressive drugs are quite different in newborns than in adults and few studies describe the pharmacokinetics of these drugs in pediatric heart transplant recipients. We report on the two-year follow up of a neonate who underwent heart transplantation for Hypoplastic Left Heart Syndrome on day of life 9. Two different immunosuppressive regimens were used: cyclosporine, azathioprine and prednisone in the early postoperative period, followed by the routine tacrolimus and mycophenolate mofetil combination plus prednisone from post-transplant day 22. Our findings demonstrate marked variability in immunosuppressive pharmacokinetic profiles early post-transplant. Frequent monitoring of drug levels is required to ensure that they remain within the therapeutic range. After the first 2-3 months post-transplant, changes in immunosuppressive drug levels are less marked and correlate more with the administered dosage. [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension is a complication of pulmonary embolism and a treatable cause of pulmonary hypertension. The pathology is a unique combination of mechanical obstruction due to failure of clot resolution, and a variable degree of microvascular disease, that both contribute to pulmonary vascular resistance. Accordingly, multiple treatments have been developed to target the disease components. However, accurate diagnosis is often delayed. Evaluation includes high-quality imaging modalities, necessary for disease confirmation and for appropriate treatment planning. All patients with chronic thromboembolic pulmonary disease, and especially those with pulmonary hypertension, should be referred to expert centres for multidisciplinary team decision on treatment. The first decision remains assessment of operability, and the best improvement in symptoms and survival is achieved by the mechanical therapies, pulmonary endarterectomy and balloon pulmonary angioplasty. With the advances in multimodal therapies, excellent outcomes can be achieved with 3-year survival of >90%., Competing Interests: Conflict of interest: N.H. Kim reports consultancy fees from Bayer, Janssen, Merck, United Therapeutics and Pulnovo, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen and Merck, participation on a data safety monitoring board or advisory board with Bayer, Janssen, Merck and United Therapeutics, and leadership roles with International CTEPH Association and CTEPH.com. A.M. D'Armini reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AOP Health and MSD, and participation on a data safety monitoring board or advisory board with AOP Health. M. Delcroix reports consultancy fees from Actelion/Janssen/J&J, Acceleron/MSD, Gossamer and Ferrer, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Actelion/Janssen/J&J, Acceleron/MSD and Ferrer. X. Jaïs reports grants from Acceleron, Janssen, MSD and Bayer HealthCare, and consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD. M. Jevnikar reports payment or honoraria for lectures, presentations, manuscript writing or educational events and support for attending meetings from Janssen and MSD. M.M. Madani reports royalties or licences from Wexler Surgical, consultancy fees from Bayer/MSD and Actelion/Janssen/J&J, and participation on a data safety monitoring board or advisory board with International CTEPH Association. H. Matsubara reports grants from Nippon Shinyaku, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, Kaneka Medix, Mochida, MSD, Nippon Shinyaku, Nipro and AOP Orphan, payment for expert testimony from MSD, participation on a data safety monitoring board or advisory board with Bayer, Janssen, Mochida and MSD, and a leadership role with International CTEPH Association. M. Palazzini reports consultancy fees, payment or honoraria for lectures, presentations, manuscript writing or educational events, and support for attending meetings from Janssen. C.B. Wiedenroth reports consultancy fees from J&J, OrphaCare and MSD, payment or honoraria for lectures, presentations, manuscript writing or educational events from J&J, AOP-Health, Bayer, Inari, MSD and Pfizer, and a leadership role with International CTEPH Association. G. Simonneau has no potential conflicts of interest to disclose. D.P. Jenkins reports consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, and and a leadership role with International CTEPH Association., (Copyright ©The authors 2024.)

Background: The European Chronic Thromboembolic Pulmonary Hypertension (CTEPH) registry, conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context., Methods: Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019., Results: Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Of patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes.s.cm -5 . During the observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention ( P <0.001). In Kaplan-Meier analysis, 3-year survival was 94%, 92%, and 71% in the 3 groups, respectively. PEA 3-year survival improved by 5% from that observed between 2007 and 2012. There was no survival difference in patients receiving vitamin K antagonists and non-vitamin K oral anticoagulants ( P =0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention., Conclusions: This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02656238., Competing Interests: M.D. reports research grants from Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Janssen, United Therapeutics, and MSD outside the submitted work, and all paid to her institution. She was holder of a Janssen chair for pulmonary hypertension at the KU Leuven. J.P.Z. reports research grants from MSD and consultant fees from Ferrer, Gossamer, Janssen outside submitted work. S.G. reports speaker fees or consultant honoraria from Actelion/Janssen, Bayer AG, MSD, and Pfizer. D.P.J. reports speaker fees and consultancy fees from Janssen outside this submitted work. D.G.K. reports speaker fees, consultancy fees, or funding to attend meetings from Acceleron, Altavant, Ferrer, Janssen, Gossamer, MSD and United Therapeutics and research support from Ferrer and Janssen, all outside of the submitted work. N.H.K. reports receiving speaker fees from Bayer and Janssen; consultancy fees from Bayer, Janssen, Merck, Polarean, Pulnovo, and United Therapeutics; and research support from Altavant and Gossamer Bio. All disclosed fees and support are outside the submitted work. M.M.M. reports consultancy fees and royalties from Wexler Surgical and consultancy fees from Actelion/Janssen and Johnson & Johnson. H.M. reports research grants from Nippon Shinyaku; speaker and consultant fees from Bayer, Janssen, and MSD; speaker fees from Kaneka Medix, Mochida, Nippon Shinyaku, and Nipro, all outside of the submitted work. J.S.O.A. reports personal fees from Bayer and MSD. R.S.K. reports having received speaker fees from AOP Health, Actelion/Janssen, and MSD, all outside of the submitted work. GS reports receiving advisory board and speaker fees from Acceleron, Bayer, Janssen, MSD, and Merck. C.B.W. reports speaker fees or consultant honoraria from Actelion/Janssen, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, OrphaCare, and Pfizer. E.M. reports receiving consultancy or speaker fees from Actelion/Janssen, Bayer, and MSD. I.M.L. has relationships with drug companies including AOP Health, Actelion/Janssen, MSD, United Therapeutics, Pulnovo, Medtronic, Neutrolis, and Sanofi; in addition to being investigator in trials involving these companies, relationships include consultancy services, research grants, and membership of scientific advisory boards. The other authors report no conflicts.

Background and objectives: Endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) play a pivotal role in the pathophysiology and vascular remodeling of chronic thromboembolic pulmonary hypertension (CTEPH) which is an under-diagnosed complication of acute pulmonary embolism (PE). Currently, pulmonary endarterectomy (PEA) is still the treatment of choice for selected patients suffering from CTEPH. The aim of this study was to evaluate the preoperative and postoperative circulating levels of ET-1 and TGF-β in subjects affected by CTEPH undergoing successful surgical treatment by PEA. Methods: The data from patients diagnosed with CTEPH who underwent PEA at the Foundation IRCCS Policlinico San Matteo Hospital (Pavia, Italy) were prospectively recorded in the Institutional database. Circulating ET-1 and TGF-β levels were assessed by an ELISA commercial kit before PEA, at 3 months and 1 year after PEA. The demographic data, preoperatory mean pulmonary arterial pressure (mPAP), cardiac output (CO), and pulmonary vascular resistance (PVR) were also recorded. Univariate and multivariate analyses were performed. Results: The analysis included 340 patients with complete ET-1 measurements and 206 patients with complete TGF-β measurements. ET-1 significantly decreased both at 3 months ( p < 0.001) and at 1 year ( p = 0.009) after PEA. On the other hand, preoperatory TGF-β levels did not significantly change after PEA. Furthermore, ET-1, but not TGF-β, was a good predictor for increased mPAP in multivariate analyses ( p < 0.05). Conclusions: ET-1 but not TGF β was significantly modulated by PEA in subjects affected by CTEPH up to 1 year after surgery. The mechanisms leading to prolonged elevated circulating TGF-β levels and their clinical significance have to be further elucidated.

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar., Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292., Findings: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%])., Interpretation: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated., Funding: Actelion Pharmaceuticals Ltd., Competing Interests: Declaration of interests H-AG has received fees for serving as a board member for AbbVie, Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, and Web MD Global; consultancy fees and fees for serving on a steering committee for Actelion Pharmaceuticals, Bayer, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, and Pfizer; lecture fees from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer; and grant support from Actelion Pharmaceuticals, Bayer, Novartis, and Pfizer. GS has received consultancy fees, lecture fees and travel support from Actelion Pharmaceuticals, Bayer, Merck, GlaxoSmithKline, and Pfizer; and grant support and fees for serving on a steering committee from Actelion Pharmaceuticals and Bayer. AMD’A has received fees for organising Masters-level courses, lecture fees and writing assistance from Bayer and Merck; and fees for serving on steering committees from Actelion Pharmaceuticals. PF has received fees for serving on an adjudication committee for Actelion Pharmaceuticals. LSH has received consultancy fees from Endotronix; fees for serving on steering committees from Actelion Pharmaceuticals, Bristol-Myers Squibb, and BTG plc; lecture fees, fees for serving on advisory boards, and travel support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, and Merck; grant support from Bayer; and departmental funding from Actelion Pharmaceuticals. XJ has received fees for serving on an adjudication committee for Actelion Pharmaceuticals; grant support from Actelion Pharmaceuticals and GlaxoSmithKline; and personal fees from Actelion Pharmaceuticals, GlaxoSmithKline, and Merck. DPJ has received fees for serving on a steering committee for Actelion Pharmaceuticals and lecture fees from Bayer. Z-CJ has received consultancy fees, lecture fees and fees for serving on a steering committee from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Lee's Pharmaceuticals, and Pfizer; fees for serving on an adjudication committee from Actelion Pharmaceuticals; and grant support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Pfizer, The National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002), and The National Key Research and Development Program of China (No. 2016YFC0901502). MMM has received fees for serving on an adjudication committee for Actelion Pharmaceuticals and consultancy fees from Bayer. NM is an employee of Actelion Pharmaceuticals. EM has received consultancy fees from Actelion Pharmaceuticals, Bayer, Merck, and GlaxoSmithKline; lecture fees from Actelion Pharmaceuticals, Bayer, Merck, Pfizer, and GlaxoSmithKline; and fees for serving on a steering committee for Actelion Pharmaceuticals. KP and DR are employees of and hold stock in Actelion Pharmaceuticals. NHK has received consultancy fees from Actelion Pharmaceuticals, Arena, Bayer, Merck, and SteadyMed; lecture fees from Actelion Pharmaceuticals and Bayer; fees for serving on a steering committee for Actelion Pharmaceuticals; and grant support from Bellerophon, Eiger, Gilead, Lung Biotechnology, and Sonivie., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

To verify whether the new hemodynamic definition of pulmonary hypertension (PH) has any implication in treatment of Chronic Thrombo-Embolic Pulmonary Disease (CTEPD) patients without PH, we retrospectively analysed the clinical and functional changes determined by pulmonary endarterectomy (PEA) in 63 CTEPD patients without PH who underwent surgery at our center, comparing those in whom the hemodynamic diagnosis of PH met recent guideline recommendations versus those in whom the diagnosis only met previous hemodynamic thresholds. The results show that the vast majority of CTEPD patients without PH operated at our center would now be defined as chronic thromboembolic pulmonary hypertension (CTEPH) patients. PEA did not result in any improvement in exercise capacity nor in right ventricular function or lung function test in patients with mean pulmonary artery pressure (mPAP) ≤ 20 mm Hg and pulmonary vascular resistance (PVR) ≤ 2 WU; on the contrary, hemodynamic parameters, exercise capacity, right ventricular function and lung function significantly improved in patients with mPAP between 21 and 24 mm Hg., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: In patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA) it is important to minimize residual obstructions, in order to achieve low postoperative pulmonary vascular resistances and better clinical results. The aim of the study was to test the hypothesis that the greater the number of pulmonary artery branches treated at surgery, the better the hemodynamic and clinical outcome after PEA., Methods: In 564 consecutive CTEPH patients undergoing PEA the count of the number of treated branches was performed directly on the surgical specimens. Post-operative follow-up visits were scheduled at 3 months and 12 months after surgery including right heart catheterization and modified Bruce test., Results: The population was divided into tertiles based on the number of treated branches: Group 1 (from 4 to 30 treated branches, n = 194 patients); Group 2 (from 31 to 43 treated branches, n = 190 patients); Group 3 (from 44 to 100 treated branches, n = 180 patients). At 3 and at 12 months after PEA, after adjustment for confounders, patients in the highest tertile of treated branches had significantly lower values of pulmonary vascular resistance and higher values of pulmonary arterial compliance as compared to the other two groups (p < 0.002). Hospital mortality was 3% in Group 3, 6% in Group 2 and 10% in Group 1 (overall p = 0.035)., Conclusions: In CTEPH patients undergoing PEA, a higher number of treated pulmonary artery branches is associated with a better hemodynamic and a better clinical outcome at 3 months and 12 months after surgery., Competing Interests: Declaration of Competing Interest the authors have no conflict of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most serious long-term complication of acute pulmonary embolism (PE) though it is the only potentially reversible form of pulmonary hypertension (PH). Its incidence is mainly limited to the first 2 years following the embolic event, however it is often underdiagnosed or misdiagnosed., Methods: This is a multicenter observational cross-sectional and prospective study. Patients with a prior diagnosis of PE will be enrolled and undergo baseline evaluation for prevalent PH detection through a clinical examination and an echocardiogram as first screening exam. All cases of intermediate-high echocardiographic probability of PH will be confirmed by right heart catheterization and then identified as CTEPH through appropriate imaging and functional examinations in order to exclude other causes of PH. A CTEPH Risk Score will be created using retrospective data from this prevalent cohort of patients and will be then validated on an incident cohort of patients with acute PE., Results: One thousand retrospective and 218 prospective patients are expected to be enrolled and the study is expected to be completed by the end of 2021. Up to now 841 patients (620 retrospective and 221 prospective) have been enrolled., Conclusions: This study is the first large prospective study for the prediction of CTEPH development in patients with PE. It aims to create a comprehensive scoring tool that includes echocardiographic data which may allow early detection of CTEPH and the application of targeted follow-up screening programs in patients with PE.

An accurate non-invasive evaluation of the mechanical properties of the vessel wall is important for a variety of screening protocols and surgical treatments. In this work, we focused on a section of the Pulmonary Artery (PA), and developed a patient-specific approach to estimate its stiffness in terms of the Young's modulus along the circumferential direction (E). First, we developed a patient-specific semi-automatic approach to estimate its expected value and standard deviation. To this end, pressure-length curves were derived from magnetic resonance images acquired during the cardiac cycle and information on vessel pressure obtained by catheterization. Then, the estimates of E were derived through a maximum likelihood estimation approach based on a vessel constitutive law. In particular, we analyzed the entire PA boundary and an arc free from surrounding organs. Second, we applied the approach to the study of pulmonary endarterectomy (PEA) for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). We observed a decrease in the circumferential E after PEA for the whole boundary, while no clear trend was observed for the free arc. The low standard deviations associated with the estimates showed high accuracy when considering the entire boundary, while greater variability was observed for the free arc, which was however limited. Finally, reliable hysteretic behavior was obtained from the reconstructed pressure-length curves., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2022 IPEM. Published by Elsevier Ltd. All rights reserved.)

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context., Methods: 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation-perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation., Results: Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA)., Conclusions: The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO., Competing Interests: Conflict of interest: S. Guth reports personal fees from Actelion, Bayer, GSK, MSD and Pfizer outside the submitted work. Conflict of interest: A.M. D'Armini reports personal fees from Actelion, Bayer and MSD outside the submitted work. Conflict of interest: M. Delcroix reports grants and personal fees from Actelion, and personal fees from Bayer, MSD, Reata and Bellarophon, outside the submitted work. Conflict of interest: K. Nakayama has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: S.P. Hoole has nothing to disclose. Conflict of interest: D.P. Jenkins reports personal fees from Actelion, and grants and personal fees from Bayer, outside the submitted work. Conflict of interest: D.G. Kiely reports grants, personal fees and nonfinancial support from Actelion, Bayer and GSK, and personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: N.H. Kim reports personal fees from Actelion, Bayer and Merck, and grants from United Therapeutics and SoniVie, outside the submitted work. Conflict of interest: I.M. Lang reports grants and personal fees from Actelion and AOPOrphan Pharma, personal fees from MSD, and nonfinancial support from Medtronic, during the conduct of the study; and grants and personal fees from Actelion and AOPOrphan, and personal fees from MSD and Ferrer, outside the submitted work. Conflict of interest: M.M. Madani is a consultant for Actelion. Conflict of interest: H. Matsubara reports personal fees from Actelion, AOP orphan Pharmaceuticals AG, Bayer, GlaxoSmithKline, Pfizer Japan, Inc., United Therapeutics, Nippon Shinyaku, Co., Ltd, and Kaneka Medix Corporation, outside the submitted work. Conflict of interest: A. Ogawa reports personal fees from Nippon Shinyaku Co., Ltd., outside the submitted work. Conflict of interest: J. Ota-Arakaki has nothing to disclose. Conflict of interest: R. Quarck has nothing to disclose. Conflict of interest: R. Sadushi-Kolici has nothing to disclose. Conflict of interest: G. Simonneau has nothing to disclose. Conflict of interest: C.B. Wiedenroth reports personal fees from Actelion, AOP, Bayer, MSD and Pfizer outside the submitted work. Conflict of interest: B. Yildizeli has nothing to disclose. Conflict of interest: E. Mayer reports personal fees from Actelion, Bayer, MSD and BMS outside the submitted work. Conflict of interest: J. Pepke-Zaba reports personal fees and nonfinancial support from Actelion and Merck, and nonfinancial support from GSK, outside the submitted work., (Copyright ©The authors 2021.)

Objectives: The aim of this study was to describe the radiological features of chronic thromboembolic pulmonary disease (CTEPD), not yet systematically described in the literature. Furthermore, we compared vascular scores between CTEPD and chronic thromboembolic pulmonary hypertension (CTEPH) patients, trying to explain why pulmonary hypertension does not develop at rest in CTEPD patients., Methods: Eighty-five patients (40 CTEPD, 45 CTEPH) referred to our centre for pulmonary endarterectomy underwent dual-energy computed tomography pulmonary angiography (DE-CTPA) with iodine perfusion maps; other 6 CTEPD patients underwent single-source CTPA. CT scans were reviewed independently by an experienced cardiothoracic radiologist and a radiology resident to evaluate scores of vascular obstruction, hypoperfusion and mosaic attenuation, signs of pulmonary hypertension and other CT features typical of CTEPH., Results: Vascular obstruction burden was similar in the two groups (p = 0.073), but CTEPD patients have a smaller extension of perfusion defects in the iodine map (p = 0.009) and a smaller number of these patients had mosaic attenuation (p < 0.001) than CTEPH patients, suggesting the absence of microvascular disease. Furthermore, as expected, the two groups were significantly different considering the indirect signs of pulmonary hypertension (p < 0.001)., Conclusions: CTEPD and CTEPH patients have significantly different radiological characteristics, in terms of signs of pulmonary hypertension, mosaic attenuation and iodine map perfusion extension. Importantly, our results suggest that the absence of peripheral microvascular disease, even in presence of an important thrombotic burden, might be the reason for the absence of pulmonary hypertension in CTEPD., Key Points: • CTEPD and CTEPH patients have significantly different radiological characteristics. • The absence of peripheral microvascular disease might be the reason for the absence of pulmonary hypertension in CTEPD., (© 2021. The Author(s).)

Aims: Aim of the study was to verify the feasibility, safety and efficacy of pulmonary endarterectomy (PEA) in octogenarian patients with chronic thromboembolic pulmonary hypertension., Methods: We retrospectively analyzed 635 chronic thromboembolic pulmonary hypertension patients who underwent PEA at our center and were followed-up for at least 1 year. The end-points of the study were in-hospital mortality, hemodynamic results at 1 year and long-term survival., Results: In-hospital mortality was 4, 10 and 17%, respectively, for 259 patients under the age of 60 years, 352 aged between 60 and 79 years and 24 octogenarians (P = 0.006 octogenarians vs. <60 years). At multivariable analysis, age and pulmonary vascular resistances were independent risk factors for mortality (P = 0.021 and P < 0.001, respectively). At 1 year, the improvement in cardiac index was lower and the distance walked in 6 min was poorer for octogenarians than for the other two groups (both P = 0.001). Survival after hospital discharge was similar over a median follow-up period of 59 months (P = 0.113). Although in-hospital mortality and long-term survival are similar in octogenarians as compared with patients aged between 60 and 79, the improvement in cardiac index and in functional capacity at 1 year are lower in this very elderly population., Conclusion: Age over 80 years should not be a contraindication to PEA surgery in selected patients operated on in referral centers., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Few studies addressed the issue of risk stratification in patients with residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). This study tested the potential added value of parameters that have not been included in existing risk models., Methods: We evaluated 546 consecutive patients with chronic thromboembolic pulmonary hypertension who underwent PEA and were followed-up for a median period of 58 months., Results: Among the 242 with residual PH, 27 died and had 127 a clinical worsening event. At univariable analysis, the parameters associated with poor survival were pulmonary vascular resistance (PVR) ≥425 dyn·s·cm -5 (p ≤ 0.001), mean pulmonary artery pressure (mPAP) ≥38 mmHg (p = 0.003) and pulmonary artery compliance (CPA) ≤1.8 ml/mmHg (p = 0.014). In the bivariable models including either PVR or mPAP as first parameter, the addition of CPA was not statistically significant. The parameters associated with poor clinical worsening were CPA ≤1.8 ml/mmHg (p < 0.001), PVR ≥425 dyn·s·cm -5 (p = 0.002), arterial oxygen tension (PaO2) ≤ 75 mmHg (p = 0.003), mPAP ≥38 mmHg (p = 0.008). In a multivariable analysis which included PVR ≥425 as the first parameter, the addition of both CPA ≤1.8 ml/mmHg and of PaO2 ≤ 75 mmHg significantly improved prognostic stratification (Harrel's C of the model = 0.64, p < 0.001). Noticeably, the lower tertile of the model's predictor index identified a subgroup of 91 patients who had an event rate numerically similar to that of patients without residual PH., Conclusions: Risk stratification in residual PH can be refined if CPA and PaO2 are considered in association with standard hemodynamic parameters., Competing Interests: Declaration of competing interest Stefano Ghio and Andrea Maria D'Armini performed consulting work for Actelion Pharmaceuticals, Ltd. and Merck Sharp Dohme. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by obstruction of the pulmonary vasculature, leading to increased pulmonary vascular resistance and ultimately right ventricular failure, the leading cause of death in non-operated patients. This article reviews the current management of CTEPH. The standard of care in CTEPH is pulmonary endarterectomy (PEA). However, up to 40% of patients with CTEPH are ineligible for PEA, and up to 51% develop persistent/recurrent PH after PEA. Riociguat is currently the only medical therapy licensed for treatment of inoperable or persistent/recurrent CTEPH after PEA based on the results of the Phase III CHEST-1 study. Studies of balloon pulmonary angioplasty (BPA) have shown benefits in patients with inoperable or persistent/recurrent CTEPH after PEA; however, data are lacking from large, prospective, controlled studies. Studies of macitentan in patients with inoperable CTEPH and treprostinil in patients with inoperable or persistent/recurrent CTEPH showed positive results. Combination therapy is under evaluation in CTEPH, and long-term data are not available. In the future, CTEPH may be managed by PEA, medical therapy or BPA - alone or in combination, according to individual patient needs. Patients should be referred to experienced centers capable of assessing and delivering all options., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change., Methods: Data from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 ), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months., Results: In 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m 2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data., Conclusions: A therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We report the case of a woman with pulmonary embolism due to a cardiac mass. Echocardiography, computed tomography scan, and cardiac magnetic resonance raised the suspicion of right atrial myxoma and confirmed the presence of pulmonary embolism. The patient was sent to the University of Pavia School of Medicine, where the atrial myxoma was excised, and, using interrupted periods of circulatory arrest, extraction of the myxoma emboli from the pulmonary arteries was performed. No adjuvant chemotherapy was required as surgical treatment is an effective therapy in cases of pulmonary embolism of a benign neoplastic mass., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: After successful pulmonary endoarterectomy (PEA), patients may still suffer from exercise limitation, despite normal pulmonary vascular resistance. We sought to assess the proportion of these patients after the extension of PEA to frail patients, and the determinants of exercise limitation., Methods: Out of 553 patients treated with PEA from 2008 to 2016 at our institution, a cohort of 261 patients was followed up at 12 months. They underwent clinical, haemodynamic, echocardiographic, respiratory function tests and treadmill exercise testing. A reduced exercise capacity was defined as Bruce test distance < 400 m., Results: Eighty patients did not had exercise testing because of inability to walk on treadmill and/or ECG abnormalities Exercise limitation 12 months after PEA was present in 74/181 patients (41, 95%CI 34 to 48%). The presence of COPD was more than double in patients with exercise limitation than in the others. Patients with persistent exercise limitation had significantly higher mPAP, PVR, HR and significantly lower RVEF, PCa, CI, VC, TLC, FEV 1 , FEV 1 /VC, D LCO , HbSaO 2 than patients without. The multivariable model shows that PCa at rest and TAPSE are important predictors of exercise capacity. Age, COPD, respiratory function parameters and unilateral surgery were also retained., Conclusions: After successful PEA, most of the patients recovered good exercise tolerance. However, about 40% continues to suffer from limitation to a moderate intensity exercise. Besides parameters of right ventricular function, useful information are provided by respiratory function parameters and COPD diagnosis. This could be useful to better address the appropriate therapeutic approach.

Objectives: The only curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). PEA requires cardiopulmonary bypass (CPB) which is associated with a high acute kidney injury (AKI) risk. Circulating endothelin-1 (ET-1) levels are elevated in CTEPH, and ET-1 plays a pivotal role in AKI. Because AKI is burdened by high morbidity and mortality, we aimed to evaluate the association between preoperative ET-1 and the risk to develop AKI in CTEPH individuals who undergo PEA. We also evaluated the association of AKI and ET-1 with kidney function and mortality at 1 year after PEA., Methods: In 385 consecutive patients diagnosed with CTEPH who underwent PEA at the Foundation IRCC Policlinico San Matteo (Pavia, Italy) from January 2009 to April 2015, we assessed preoperative circulating ET-1 by ELISA and identified presence of AKI based on 2012 KDIGO criteria., Results: AKI occurred in 26.5% of the 347 patients included in the analysis, and was independently associated with preoperative ET-1 (p = 0.008), body mass index (BMI) (p = 0.022), male gender (p = 0.005) and duration of CPB (p = 0.002). At 1-year post PEA, estimated glomerular filtration rate (eGFR) significantly improved in patients who did not develop AKI [ΔeGFR 5.6 ml/min/1.73 m 2 (95% CI 3.6-7.6), p < 0.001] but not in those with perioperative AKI. AKI (p < 0.001), age (p < 0.001), preoperative eGFR (p < 0.001) and systemic hypertension diagnosis (p = 0.015) were independently associated with 1-year ΔeGFR. Neither perioperative AKI nor preoperative ET-1 was associated with 1-year survival., Conclusion: Perioperative AKI is associated with higher preoperative circulating ET-1 and it negatively influences long-term kidney function in patients with CTEPH who undergo PEA.

Background: It has been hypothesized that pre-capillary pulmonary hypertension (PH) may trigger sleep disordered breathing (SDB). In patients with chronic thromboembolic PH (CTEPH), pulmonary endarterectomy (PEA) is potentially effective to improve PH. We assessed the pre- and post-operative prevalence of SDB in CTEPH patients submitted to PEA and the relationship between SDB and clinical, pulmonary and hemodynamic factors., Methods: Unattended cardiorespiratory recording was performed the night before and one month after elective PEA in 50 patients., Results: Before the intervention SDB prevalence (obstructive or central AHI ≥ 5/h) was 64%: 18 patients (66% female) had No-SDB, 22 (68% female) had dominant obstructive (dOSA), and 10 (20% female) had dominant central sleep apnea (dCSA). There were no differences in risk factors and the need for supplemental oxygen. Mean right atrial (mRAP) and pulmonary artery pressures (mPAP) showed a more compromised profile from No-SDB to dOSA and dCSA (mRAP: 5.5 ± 3.9 vs 7.0 ± 4.5 vs 9.7 ± 4.3 mm Hg (p = 0.054), mPAP: 39 ± 12 vs 48 ± 11 vs 51 ± 16 mm Hg (p = 0.0.47)). By contrast, cardiac index did not differ. At post-intervention, the prevalence of SDB was 68%: 16 patients had No-SDB, while 30 had dOSA and 4 dCSA, with no relationship with the relief from PH. Interestingly, 5 patients with previous CSA moved to the OSA group and 2 normalized., Conclusions: Prevalence of SDB is high in patients with CTEPH even after resolution of PH. Our data support the hypothesis that pre-capillary PH may trigger CSA but not OSA, and suggest that OSA may play a role in the development of CTEPH., (Copyright © 2018. Published by Elsevier B.V.)

Background: In this prospective, single-center, observational study, we investigated the association between repeated short periods of circulatory arrest with moderate hypothermia during pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and different neuropsychological dimensions., Methods: We examined 70 patients with CTEPH, >18 to 80 years of age, who had been treated with PEA. Neuropsychological testing was performed., Results: Learning ability and delayed memory remained well within the normal range for patients' age. We found a statistically significant post-surgical improvement in motor speed, which was accompanied by a better quality of life and reduced symptoms of depression and anxiety., Conclusion: PEA with repeated short periods of circulatory arrest in CTEPH did not result in any neuropsychological complications and may even lead to post-surgical psychological improvements., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Malignancies are one of the leading causes of death in long-term surviving transplant recipients. Dose and prolonged durations of immunosuppressive regimens are considered the main cause, through a direct oncogenic effect and a renowned interaction on physiological anti-viral and anti-oncogenic immune response. Specific neoplasms are known to occur with different frequencies according to the transplanted organ. As a consequence, imaging screenings have been implemented in many graft surveillance programs, although a wide consensus on the timing and modality has not been concurred. There are little data available in the literature regarding incidence of de-novo malignancies in multi-organ recipients. We report the case of a 66-year-old man who developed a renal mass 10 years after a combined heart-kidney transplant.

Background: Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH., Methods: We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints., Results: In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean ± standard deviation 6MWD had increased by 33 ± 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups., Conclusions: Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed., Trial Registration: ClinicalTrials.org NCT01784562 . Registered February 4, 2013.

In our experience, we reperformed pulmonary endarterectomy (PEA) in 10 patients who previously underwent a first PEA. We analyzed this cohort of patients to investigate the main causes of recurrence of symptomatic pathology and the clinical and hemodynamic results of redo surgery. Between 1994 and April 2016, 10 of 716 patients were reoperated at our institution. Available postoperative data were analyzed, and a comparison between first and second PEA hemodynamic and clinical results was carried out. In-hospital mortality rate was also evaluated. After reoperation, mean pulmonary arterial pressure decreased from 45?±?9 to 34?±?10?mm Hg, and pulmonary vascular resistance reduced from 932?±?346?dyne*s*cm ?5 to 428?±?207?dyne*s*cm ?5 . Hemodynamic data revealed worthy results of redo PEA, although they are less important than after first PEA. The World Health Organization (WHO) functional class improvement demonstrated satisfactory clinical results. In-hospital mortality of repeat PEA is 40%. Reoperative PEA operative candidacy should be assessed in case of young patients, no other risk factor, and recent medical history of pulmonary hypertension. In the other cases, in-hospital mortality rate is very high and pulmonary hypertension-specific drug therapy or interventional approach should be previously considered., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar., Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292., Findings: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70-0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%])., Interpretation: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated., Funding: Actelion Pharmaceuticals Ltd., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The role of CD4 + CD25 high CD127 - T-reg cells in solid-organ Transplant (Tx) acceptance has been extensively studied. In previous studies on kidney and liver recipients, peripheral T-reg cell counts were associated to graft survival, while in lung Tx, there is limited evidence for similar findings. This study aims to analyze long term peripheral kinetics of T-reg-cells in a cohort of lung recipients and tests its association to several clinical variables., Methods: From jan 2009 to dec 2014, 137 lung Tx recipients were submitted to an immunological follow up (median: 105.9 months (6.7-310.5)). Immunological follow up consisted of a complete blood peripheral immuno-phenotype, inclusive of CD4 + CD25 high CD127 - T and FOXP3+ cells. We tested the association between T-reg and relevant variables by linear OR regression models for repeated measures, adjusting for time from Tx. Also, by ordered logistic models for panel data, the association between Chronic Lung Allograft Dysfuncton (CLAD) onset/progression and T-reg counts in the previous 3 months was tested., Results: Among all variables analyzed at multivariate analysis: Bronchiolitis Obliterans Syndrome (OR -6.51, p < 0.001), Restrictive Allograft Syndrome (OR -5.19, p = 0.04) and Extracorporeal photopheresis (OR -5.65, p < 0.001) were significantly associated to T-reg cell. T-reg cell counts progressively decreased according to the severity of CLAD. Furthermore, patients with higher mean T-reg counts in a trimester had a significantly lower risk (OR 0.97, p = 0.012) of presenting CLAD or progressing in the graft dysfunction in the following trimester., Conclusions: Our present data confirm animal observations on the possible role of T-reg in the evolution of CLAD.

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, is the third most common cause of cardiovascular death. The management of the acute phase of VTE has already been described in several guidelines. However, the management of the follow-up (FU) of these patients has been poorly defined. This consensus document, created by the Italian cardiologists, wants to clarify this issue using the currently available evidence in VTE. Clinical and instrumental data acquired during the acute phase of the disease are the cornerstone for planning the FU. Acquired or congenital thrombophilic disorders could be identified in apparently unprovoked VTE during the FU. In other cases, an occult cancer could be discovered after a VTE. The main targets of the post-acute management are to prevent recurrence of VTE and to identify the patients who can develop a chronic thromboembolic pulmonary hypertension. Knowledge of pathophysiology and therapeutic approaches is fundamental to decide the most appropriate long-term treatment. Moreover, prognostic stratification during the FU should be constantly updated on the basis of the new evidence acquired. Currently, the cornerstone of VTE treatment is represented by both the oral and the parenteral anticoagulation. Novel oral anticoagulants should be an interesting alternative in the long-term treatment.

Objective: We compared the haemodynamic effects of riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy in the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 study., Methods: Patients with inoperable or persistent/recurrent CTEPH (n=261; mean± SD age 59±14 years; 66% women) were randomised to riociguat (up to 2.5 mg three times daily) or placebo. Haemodynamic parameters were assessed at baseline and week 16., Results: Riociguat decreased pulmonary vascular resistance (PVR) in inoperable (n=189; least-squares mean difference: -285 dyn s/cm 5 (95% CI -357 to -213); p<0.0001) and persistent/recurrent (n=72; -131 dyn s/cm 5 (95% CI -214 to -48); p=0.0025) patients. Cardiac index improved in inoperable patients by a least-squares mean difference of +0.6 L/min/m 2 (95% CI 0.4 to 0.7; p<0.0001), while in persistent/recurrent patients the change was +0.2 L/min/m 2 (95% CI -0.1 to 0.5; p=0.17). Mean pulmonary artery pressure decreased in inoperable and persistent/recurrent patients(-4.7 mm Hg (95% CI -6.9 to -2.6; p<0.0001 and -4.8 mm Hg (-8.2 to -1.5; p=0.0055), respectively). For all patients, changes in 6 min walk distance correlated with changes in PVR (r=-0.29 (95% CI -0.41 to -0.17); p<0.0001) and cardiac index (r=0.23 (95% CI 0.10 to 0.35); p=0.0004)., Conclusions: Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH., Trial Registration Number: NCT00855465., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension, resulting from fibrotic transformation of pulmonary artery clots causing chronic obstruction in macroscopic pulmonary arteries and associated vascular remodelling in the microvasculature.Pulmonary endarterectomy (PEA) offers the best chance of symptomatic and prognostic improvement in eligible patients; in expert centres, it has excellent results. Current in-hospital mortality rates are <5% and survival is >90% at 1 year and >70% at 10 years. However, PEA, is a complex procedure and relies on a multidisciplinary CTEPH team led by an experienced surgeon to decide on an individual's operability, which is determined primarily by lesion location and the haemodynamic parameters. Therefore, treatment of patients with CTEPH depends largely on subjective judgements of eligibility for surgery by the CTEPH team.Other controversies discussed in this article include eligibility for PEA versus balloon pulmonary angioplasty, the new treatment algorithm in the European Society of Cardiology/European Respiratory Society guidelines and the definition of an "expert centre" for the management of this condition., (Copyright ©ERS 2017.)

Introduction: Pulmonary artery sarcoma (PAS) is a rare tumor, whose therapeutic approach is mainly based on surgery, either pneumonectomy or pulmonary endarterectomy (PEA). The prognosis reported in published series is very poor, with survival of 1.5 months without any kind of treatment., Patients and Methods: From January 2010 to January 2016, 1027 patients were referred to our hospital for symptoms of acute or chronic pulmonary thromboembolic disease. Twelve patients having a confirmed diagnosis of PAS underwent PEA. Median age was 64.5 years. Most patients had a long history of symptoms, having a median time of 7.5 months from onset of symptoms to surgery., Results: Following PEA and cardiopulmonary rehabilitation, 10 patients received conventional chemotherapy with doxorubicin and ifosfamide, starting at a median of 42 days from surgery. Four patients also received radiotherapy. Four patients have died due to disease progression, while 7 are still alive, with 5 being disease-free at 4-55+ months from diagnosis., Conclusions: In patients with PAS, a multimodal approach including PEA, CT, and RT is feasible but it should be evaluated individually, according to the tumor extension and the patient's clinical condition. Apart from improving quality of life mainly by reducing or delaying symptoms due to PH, it may improve life expectancy.

Pulmonary endarterectomy is the gold standard treatment for chronic thromboembolic pulmonary hypertension and is potentially curative, although some patients are unsuitable for pulmonary endarterectomy and require alternative management. Lack of standardized assessment of pulmonary endarterectomy eligibility risks suboptimal treatment in some patients. We discuss the implications for future clinical trials and practice of a unique operability assessment in patients who have chronic thromboembolic pulmonary hypertension and were initially screened for inclusion in the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial-1) study. The CHEST-1 study evaluated riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. Screened patients who were initially considered "inoperable" underwent central independent adjudication by a committee of experienced surgeons, or local adjudication in collaboration with an experienced surgeon. Operability decisions were based on accessibility of thrombi and the association between pulmonary vascular resistance (PVR) and the extent of obstruction, using pulmonary angiography/computed tomography with ventilation/perfusion scintigraphy as the minimum diagnostic tests. Of 446 patients screened for CHEST-1, a total of 188 and 124 underwent central and local adjudication, respectively, after being initially considered to be "inoperable." After a second assessment by an experienced surgeon, 69 of these 312 "inoperable" patients were deemed operable. Rigorous measures in CHEST-1 guaranteed that only technically inoperable patients, or patients who had persistent/recurrent pulmonary hypertension, were enrolled, thus ensuring that only patients for whom surgery was not an option were enrolled. This study design sets new standards for future clinical trials and practice in CTEPH, helping to ensure that patients who have CTEPH receive optimal treatment., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received riociguat for at least 2 years., Methods: Eligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429., Findings: 237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89-96) and clinical worsening-free survival was 82% (77-87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued riociguat therapy because of adverse events., Interpretation: Riociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers., Funding: Bayer Pharma AG., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The aim of the present study was to evaluate the changes of electrocardiographic (ECG) markers of right ventricular (RV) hypertrophy/overload in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA)., Methods and Results: We evaluated 99 CTEPH patients who underwent PEA. P wave amplitude in DII, R wave amplitude in V1 and the number of patients with negative T wave in V1-V3 decreased significantly at 1month after surgery with no further change at 1year, in parallel with the rapid improvement in right heart hemodynamics. S wave amplitude in V1, R:S wave ratio in lead V6 and prevalence of SIQIII pattern improved significantly at 1year, in parallel with the progressive reverse remodeling of the right ventricle at echocardiography., Conclusions: The study shows that some of the ECG markers of RV hypertrophy/overload better reflect RV hemodynamic overload while others better reflect the pathologic remodeling of the right ventricle., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension., Methods and Results: A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90-95), 91% (95% CI, 87-93), and 89% (95% CI, 86-92) in operated patients (n=404), and only 88% (95% CI, 83-91), 79% (95% CI, 74-83), and 70% (95% CI, 64-76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension-targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49-11.62; P=0.0065 and HR, 4.76; 95% CI, 1.76-12.88; P=0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95-1.90; P=0.0992 and HR, 1.50; 95% CI, 1.20-1.88; P=0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36-6.69; P=0.0065 and HR, 2.15; 95% CI, 1.18-3.94; P=0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension-targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients., Conclusions: The long-term prognosis of operated patients currently is excellent and better than the outcome of not-operated patients., (© 2016 American Heart Association, Inc.)

Background: Early rehabilitation after cardiac surgery aims to prevent immobilization, to reduce the effects of surgery on the respiratory function and to facilitate the recovery of autonomy in the activities of daily living (ADL), after discharge. Nevertheless the optimal perioperative physical therapy care for patients undergoing cardiac surgery is not well established. Moreover, most of the studies monitored peripheral oxygen saturation (SpO2) and heart rate (HR) during surgery or focused only on their recovery after rehabilitation and not on their pathways during a session of exercises., Aim: To monitor peripheral oxygen saturation and HR before, during and at the end of a single session of early rehabilitation after cardiac surgery, so testing our protocol's safety., Design: A case series., Setting: Department of Cardiothoracic Surgery, inpatients., Population: Forty-eight consecutive inpatients (35 M), mean age 61 years, with cardiovascular disease (CVD), who underwent cardiac surgery., Methods: We monitored SpO2%, HR, systemic blood pressure (BP), pain in the thoracic wound (VAS) and rate of perceived exertion (RPE) during the rehabilitation session after weaning from oxygen therapy., Results: During all phases mean SpO2 was 94% (±1.8) and mean HR was 85 bpm (±13.3). Number of desaturation events were 14 in total and mean of % of time with SpO2<90% was 3 (±6.5) during all the rehabilitative session. Moreover, mean BP after reaching the sitting position was 124.7 (±11.9)/78.6 (±8.4) and after ambulation was 131.5 (±11.5)/82.9 (±7.3)., Conclusion: The monitoring peripheral oxygen saturation and HR during and not only before and at the end of a standardized early rehabilitation session helped us to ensure the safety of our protocol., Clinical Rehabilitation Impact: Because of its feasibility, safety and reproducibility our rehabilitation treatment has been applied to different types of surgical inpatients in order to limit the negative consequences of immobilization.

Aims: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension, but there are few data in the literature about the results of this procedure in the elderly. In this study, we aimed to assess whether this type of surgery is effective and well tolerated for the elderly., Methods: A total of 264 consecutive patients who underwent PEA between January 2008 and December 2012 were reviewed. PEA was performed under cardiopulmonary bypass and hypothermic ventricular fibrillation, with the aorta left unclamped. The population was dichotomized according to age into the following two groups: below 70 years (n = 176, younger patients) and at least 70-year-olds (n = 88, elderly patients). Regression models were used to identify predictors of hospital mortality and postoperative adverse events, and their interaction with age was tested., Results: Hospital mortality was slightly, but not significantly higher in elderly patients (9.1 vs. 5.1%; P = 0.22). Effect modification by history of smoking and preoperative O2 therapy was present. The cumulative survival at 1, 2, and 4 years was 93, 92, and 91% among younger patients; and 88, 86, and 86% among older patients (P = 0.19). Clinical and hemodynamic improvement was similar in the two groups., Conclusion: Despite a slightly higher short-term mortality, PEA is feasible and well tolerated for the vast majority of the elderly patients. Clinical and hemodynamic improvements are outstanding, with satisfactory long-term survival rates.

Background: Surgical procedure and postoperative bed rest lead to musculoskeletal system alterations with a possibility of new walking dependence of patients who undergo cardiothoracic surgery, which is sometimes associated with prolonged hospitalization and increased health expenditure., Aim: The aim of this study was to assess the postoperative motor disability in inpatients admitted to the cardiothoracic surgical ward, and the results of customized rehabilitation in terms of recovery of postural changes and walking capacity with respect to the preoperative condition and destination after discharge., Design: A prospective observational study was conducted., Setting and Population: Four hundred seventeen inpatients, who had undergone cardiothoracic surgery, were enrolled between March 2011 and January 2012 in a Hospital Unit of Cardiothoracic Surgery., Methods: A computerized system was used to collect data about ambulation at home, type and number of rehabilitation sessions proposed, ambulation at discharge, destination after discharge from ward of origin. All patients, who give their consent, undergone rehabilitative treatment on the ward of origin with an expert physiotherapist., Results: Three hundred seventy-five inpatients were examined in Cardiac Surgery. One patient (0.26%) refused rehabilitative treatment. Two patients (0.53%) died. At the time of discharge 236 (74.45%) patients had recovered the ability to walk independently. After discharge 87.64% of patients was transferred to a specialist ward for intensive rehabilitation. Forty-two inpatients were enrolled in thoracic surgery. Two patients died whilst in hospital. At the time of discharge, 36 patients (94.73%) were able to walk independently. After discharge 80% of patients returned home., Conclusion: In our study, the application of an early and simple rehabilitation program on the ward of origin after surgery has made possible the recovery of ambulation of most inpatients who referred independence at home in a few days, limiting hospitalization and health expenditure., Clinical Rehabilitation Impact: Data about recovery of ambulation with respect to the preoperative condition and destination after discharge resume the importance of identifying motor impairment after surgery, in order to apply an adequate, early and feasible rehabilitation protocol to inpatients, limiting hospitalization and health expenditure.

Purpose: The study investigates Quality of Life (QOL) and correlation with functional status of patients affected by Chronic Thromboembolic Pulmonary Hypertension who undergo Pulmonary Endoarterectomy., Methods: We investigated with an observational design (before surgery, three and twelve months afterwards) the hemodynamic data (NYHA class, mean pulmonary arterial pressure, cardiac output and pulmonary vascular resistance), the functional status (using the 6-Minute Walk Test) and the QOL, using three questionnaires: Medical Outcome Study Short Form-36 (SF-36), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Saint George Respiratory Questionnaire (SGRQ). We report the results of forty-nine patients., Results: After surgery there was an improvement on functional and hemodynamic parameters and on QOL. The physical domain (PCS) of SF-36 was weakly but significantly associated with all functional parameters. There was no association between functional parameters and mental domain (MCS) of SF-36 or SGRQ. The improvement in 6-Minute Walk Distance was associated with an increase in MLHFQ., Conclusions: Both QOL and submaximal exercise tolerance improve after surgery. However only the physical domains of SF-36 appear to be significantly associated to the functional data.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the presence of thromboembolic material in the pulmonary circulation, and patients have a poor prognosis without treatment. Patients present with nonspecific symptoms, such as breathlessness and syncope, which means that other more common conditions are sometimes suspected before CTEPH, leading to delayed diagnosis and treatment. This is problematic because CTEPH is potentially curable with surgical pulmonary endarterectomy (PEA); indeed, CTEPH should always be considered in any patient with unexplained pulmonary hypertension (PH). Several key evaluations are necessary and complementary to confirm a diagnosis of CTEPH and assess operability. Echocardiography is initially used to confirm a general diagnosis of PH. Ventilation/perfusion scanning is then essential in the first stage of CTEPH diagnosis, with a wedge-shaped perfusion deficit indicative of CTEPH. This should be followed by right heart catheterisation (RHC) which is mandatory in confirming the diagnosis and providing haemodynamic parameters that are key predictors of the risk associated with PEA and subsequent prognosis. RHC is ideally coupled with conventional pulmonary angiography, the gold-standard technique for confirming the location and extent of disease, and thus whether the obstruction is surgically accessible. Computed tomographic pulmonary angiography is also now routinely used as a complementary technique to aid diagnosis and operability assessment. Recent improvements in the resolution of other noninvasive techniques, such as cardiac magnetic resonance imaging, allow for detailed reconstructions of the vascular tree and imaging of vessel defects, and interest in their use is increasing., (Copyright ©ERS 2015.)

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit-risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit-risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year., (Copyright ©ERS 2015.)