Pulmonary Veno-occlusive Disease Research Articles

Patient-specific and gene-corrected induced pluripotent stem cell-derived endothelial cells elucidate single-cell phenotype of pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterized by the preferential remodeling of the pulmonary venules. Hereditary PVOD is caused by biallelic variants of the EIF2AK4 gene. Three PVOD patients who carried the compound heterozygous variants of EIF2AK4 and two healthy controls were recruited and induced pluripotent stem cells (iPSCs) were generated from human peripheral blood mononuclear cells (PBMCs). The EIF2AK4 c.2965C>T variant (PVOD#1), c.3460A>T variant (PVOD#2), and c.4832_4833insAAAG variant (PVOD#3) were corrected by CRISPR-Cas9 in PVOD-iPSCs to generate isogenic controls and gene-corrected-iPSCs (GC-iPSCs). PVOD-iPSC-endothelial cells (ECs) exhibited a decrease in GCN2 protein and mRNA expression when compared with control and GC-ECs. PVOD-ECs exhibited an abnormal EC phenotype featured by excessive proliferation and angiogenesis. The abnormal phenotype of PVOD-ECs was normalized by protein kinase B inhibitors AZD5363 and MK2206. These findings help elucidate the underlying molecular mechanism of PVOD in humans and to identify promising therapeutic drugs for treating the disease.

A rare compound heterozygous EIF2AK4 mutation in pulmonary veno-occlusive disease

BackgroundPulmonary veno-occlusive disease (PVOD) is a rare, progressive, and oft-fatal condition of pulmonary arterial hypertension that is typically difficult to diagnose and treat. However, with the development of next-generation sequencing technology, an increasing number of patients with PVOD are being diagnosed.MethodsInitially, we used whole exome sequencing (WES) to identify the proband as a rare compound heterozygous mutation of EIF2AK4 in PVOD. Subsequently, the parents of patient underwent EIF2AK4 screening by Sanger sequencing.ResultsIn this study, we describe the family tree of a patient with PVOD with a rare compound heterozygous EIF2AK4 mutation. Moreover, we identified a new EIF2AK4 mutation, c.2236_2237insAAGTCCTTCT, in exon 12 of the proband and his mother. This frameshift mutation led to premature termination of the coding protein sequence and widespread loss of protein function, which promoted the development of PVOD.ConclusionsOur results expand our understanding of the EIF2AK4 mutation spectrum in patients with PVOD, as well as highlight the clinical applicability of WES.

Characteristics of Patients With Pulmonary Arterial Hypertension in a Pulmonary Hypertension Association-Accredited Comprehensive Care Center: A Contrast in Features When Compared With US National Registry Data.

Background Since the initial description in the 1980s, our understanding of the diversity of pulmonary arterial hypertension (PAH) has continued to evolve. In this study, we report the characteristics of patients seen in an academic medical center for PAH from August 2020 through November 2021 and contrast those with nationally reported data from the United States Pulmonary Hypertension Scientific Registry (USPHSR). Study Design Investigators at the University of Utah Pulmonary Hypertension Program prospectively enrolled adult patients diagnosed with WHO Group 1 PAH, who were evaluated between August 2020 and November 2021 in a program-specific registry. Patient exposure and health histories were collected through structured interviews and questionnaires, along with clinical data and medication use. A total of 242 patients were enrolled in the University of Utah Pulmonary Hypertension Registry (UUPHR). Results Of the 242 enrolled patients, the most common etiology was associated PAH (APAH), accounting for 71.1% of the population. The second largest etiology was idiopathic PAH (IPAH) at 26.4%. The remaining patients were distributed between familial PAH (FPAH), pulmonary veno-occlusive disease (PVOD), and others. Of the total population classified as APAH, 39% of cases were noted as secondary to connective tissue disease (CTD) and 33% as toxin-induced. These represented 28% and 24% of the total population, respectively. Conclusions In this US-based accredited academic medical center, the etiology of PAH in our patient population contrasts with national registry data. In the UUPHR, APAH, specifically CTD-PAH and toxin-associated PAH, accounts for the majority of patients with PAH. This contrasts with IPAH, which nationally is the most reported cause of PAH. Differences in our population may reflect the regional variation of the referral site, but it is noteworthy for its contrast with historically reported phenotypes.

First genetic characteristics of Polish patients with idiopathic pulmonary arterial hypertension

Abstract Introduction Pulmonary arterial hypertension (PAH) is a rare, severe disorder of multifactorial origin. Genetic alterations in BMP/SMAD pathways were previously associated with disease development, however the exact role of other genetic factors from BMP/SMAD signalling is still unclear. Purpose We aimed to search for known PAH-associated mutations and potential novel variants responsible for disease onset in Polish PAH patients. Methods We prospectively recruited 93 consecutive idiopathic PAH patients from a single pulmonary hypertension reference centre between years 2009 and 2020. Eligible patients had pre-capillary pulmonary hypertension with pulmonary vascular resistance >3 Wood units in the absence of other causes of pre-capillary pulmonary hypertension. The presence of large gene rearrangements was analyzed by the Multiplex Ligation-dependent Probe Amplification (MLPA) reactions in the ENG, ACVRL1 and BMPR2 genes (SALSA MLPA Kit, MRC-Holland). We have further sequenced a panel of selected 48 genes from BMP/SMAD and related pathways using next-generation sequencing (SureSelect XT library preparation Kit, Agilent; NextSeq 500 sequencer, Illumina) and assessed causative potential of rare variants (minor allele frequency in non-finish Europeans below 1%) with Mutation Taster web-based tool. Results We identified at least one likely-causative variant of investigated genes in 51 (54.8%) subjects. Large genomic rearrangements were found by MLPA in 2 patients in ENG and ACVRL1 (ALK1) genes. We have found mutations in BMPR2 gene in 12 patients (12.5%) from our cohort with most variants present in one sample and 3 variants present in 2 samples. Mutations were located mostly in protein kinase domain (6 variants) and Activin type I and II receptor domain (2 variants). We have found 5 likely pathogenic variants in 6 patients in genes previously associated with PAH other than BMPR2 (SMAD9, KCNA5, KCNK3, EIF2AK4). In total, potentially disease causing mutations in literature-known genes, were present in 18 patients, which accounted for 18.75% of tested cohort. Medium impact variants were also present in KCNA5, TGFBR2, AQP7, BMP6, EIF2AK4, FBP1, NOTCH1, NOTCH3, SMAD7, TBX4, TGFB2, TOPBP1, GDF5, IL6, PPARA, RXRA, KCNK3, KLF4, BMPR1B, ILK, TGFBR1, SMAD9, PPARD and TGFB3 genes. Additionally, in one patient with clinical diagnosis of pulmonary venoocclusive disease we identified an unknown homozygous frameshift variant (p.Phe1523fs/c.4567_4570delTTTG) in exon 35 of EIF2AK4 gene. Conclusions We found potentially disease causing mutations in 18,75% Polish patients diagnosed with IPAH most of them were present in BMPR2 gene which is in line with data from other European cohorts. Additionally we found an unknown mutation in the EIF2AK4 gene. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Narodowe Centrum Nauki - National Science Centre

PULMONARY CAPILLARY HEMANGIOMATOSIS: A CONUNDRUM FOR EXPERTS

PULMONARY CAPILLARY HEMANGIOMATOSIS: A CONUNDRUM FOR EXPERTS

Efficacy and safety of oral pulmonary vasodilators in pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH) is a rare subtype of pulmonary hypertension with dismal prognosis. Limited data are available on the efficacy and safety of orally administered pulmonary vasodilators for PVOD/PCH. Whether and how systemic sclerosis (SSc) affects the clinical outcomes of PVOD/PCH is also unknown. This study aimed to determine the clinical and hemodynamic efficacy and safety of oral pulmonary vasodilators for PVOD/PCH and clarify the possible effects of SSc on the clinical presentation of PVOD/PCH. We retrospectively analyzed the clinical data of 15 patients with PVOD/PCH treated with oral pulmonary vasodilators in our department since 2001. Six of them had SSc. Oral pulmonary vasodilators were administered either as single agents (n = 10) or in combination (n = 5). Treatment improved the functional class of five patients, and pulmonary arterial pressure and pulmonary vascular resistance decreased by 10 ± 12 mmHg and 36 ± 19%, respectively (p < 0.05 for both, n = 13), whereas pulmonary edema developed in three patients. The mean survival was 3.9 years, and the 1- and 3-year survival rates were 93% and 65%, respectively. The clinical presentation, including survival, was similar between patients with and without SSc. In our PVOD/PCH cohort, oral pulmonary vasodilators caused pulmonary edema in 20% of patients, but more than 80% of patients experienced significant pulmonary vasodilatory effects, and the overall prognosis was better than that previously reported. SSc does not adversely affect the clinical outcomes of PVOD/PCH.

Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry.

Background: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. Objectives: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. Methods: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan–Meier curves. Results: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease—PVOD—in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders—MSD—in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was “reclassified”, with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. Conclusions: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.

Risk stratification in patients with pulmonary arterial hypertension at the time of listing for lung transplantation.

It is unknown whether pulmonary arterial hypertension (PAH) risk stratification instruments could be helpful to support the decision to list a patient for lung transplantation (LT). Our aim was to evaluate contemporary risk assessment tools in a cohort of PAH patients listed for LT. Consecutive PAH patients (without pulmonary veno-occlusive disease or unrepaired congenital heart disease) listed for LT at the French Pulmonary Hypertension Reference Center between January 2006 and December 2018 were included. At the time of listing, risk stratification was assessed using the ESC/ERS criteria, the REVEAL Lite 2 score and the COMPERA 2.0 method. The primary end point was overall survival after LT listing. Secondary outcome measures were mortality on waiting list and posttransplant survival. One hundred and two patients were enrolled (mean age 38 ± 13 years, 69% females). Overall survival after listing was 72%, 58% and 46% at 1, 3 and 5 years respectively. Survival after LT listing was lower in "high-risk" patients according to the ESC/ERS criteria (p=0.0001) and the REVEAL Lite 2 score (p=0.04). The COMPERA 2.0 method discriminated post-listing survival of patients at high-risk, intermediate-high and intermediate-low risk (p=0.04). The proportion of patients requiring urgent transplantation and extracorporeal life support as a bridge to transplantation was higher in the "high-risk" patients. Posttransplant survival was significantly lower in "high-risk" patients according to the ESC/ERS criteria (p=0.0004). High-risk PAH patients at the time of LT listing have poor outcomes, suggesting that LT should be considered earlier in the course of PAH remaining refractory to triple combination therapy with a parenteral prostacyclin.

Pulmonary Capillary Haemangiomatosis: A Rare Cause of Pulmonary Hypertension

Pulmonary capillary haemangiomatosis (PCH) is a rare disorder of unknown aetiology, characterised by proliferating capillaries that invade the pulmonary interstitium, alveolar septae and the pulmonary vasculature. It is often mis-diagnosed as primary pulmonary hypertension and pulmonary veno-occlusive disease. Pulmonary capillary haemangiomatosis is a locally aggressive benign vascular neoplasm of the lung. We report the case of a 19-year-old female who was referred to us in the early post-partum period with severe pulmonary artery hypertension, which was diagnosed as PCH by open lung biopsy.

Severe Right Heart Failure in a Patient with Chronic Obstructive Lung Disease: A Diagnostic Challenge

A 55-year-old male was admitted for evaluation of severe dyspnoea and hypoxaemia. Physical examination upon admission showed elevated jugular venous pressure and an accentuated second heart sound. Chest radiograph showed cardiomegaly with increased bibasilar markings. Arterial blood gas analysis while breathing room air showed marked hypoxaemia. High resolution computed tomography angiography of the chest showed modestly enlarged mediastinal lymph nodes with discrete diffuse ground-glass attenuation especially at the lower lung zones. Positron emission tomography using 18F labelled 2-deoxy-D-glucose (FDG) demonstrated the mediastinal lymph nodes were FDG-avid. Transthoracic echocardiography showed dilated hypokinetic right heart chambers with bulging of the interventricular septum to the left, compatible with acute cor-pulmonale. From the tricuspid regurgitation jet measurement a systolic pulmonary artery pressure (PAP) of 48 mmHg was estimated. Patent foramen ovale was suspected on bubble test. Right heart catheterisation confirmed pulmonary arterial hypertension: mPAP 47 mmHg, pulmonary artery occlusion pressure 5 mmHg, cardiac index 1.1 L/min/m2, pulmonary vascular resistance (PVR) 959 dyne.sec.cm(-5). Pulmonary function tests showed a marked diffusing capacity for carbon monoxide (DLCO) decrease of 32% predicted but no obstructive lung deficit. Before an open lung biopsy could be scheduled the patient developed acute cardiogenic shock. At autopsy pulmonary veno-occlusive disease with marked pulmonary hypertension was diagnosed.

A Systematic Review on Pulmonary Complications Secondary to Hematopoietic Stem Cell Transplantation.

The main purpose of this systematic review was to identify and synthesize evidence about pulmonary complications following stem cell transplantation to raise awareness among physicians since it is a lesser-known topic. Studies that included targeted pulmonary complications that occurred after stem cell transplantation; in humans; and were randomized controlled trials, cohort studies, and case studies between January 2011 and 2021. Fifteen intervention features were identified and analyzed in terms of their association with successful or unsuccessful interventions. Fifteen of 15 studies that met inclusion criteria had positive results. Features that appeared to have the most consistent positive effects included relevant information consisting of clinical presentations and management of complications. Hematopoietic stem cell transplantation is a therapeutic method that has been introduced for various hematological diseases. Its main objective is to restore the hematopoietic function that has been eradicated or affected. The stem cell transplantation requires a period of administration of chemotherapeutic agents that may lead to infectious and/or non-infectious pulmonary complications that require follow-up.Noninfectious pulmonary complications include bronchiolitis obliterans, alveolar hemorrhage, fibroelastosis, pulmonary hypertension, and infections. Bronchiolitis obliterans syndrome is an obstructive lung disease that affects the small airways, reducing lung function, and it’s the most frequent late-onset complication. Furthermore, diffuse pulmonary hemorrhage is a fatal adverse effect and the most common noninfectious pulmonary complication of acute leukemia, observed within the first weeks after the procedure. Pulmonary hypertension has multiple etiologies, mainly related to the pulmonary veno-occlusive disease. It carries a poor prognosis, with a 55% mortality rate. The area of hematology is very wide and prone to new development of treatments and procedures that could be available for new emerging diseases and improving survival rates.

Lung Transplant Outcomes in Patients with Pulmonary Veno-Occlusive Disease

<h3>Purpose</h3> Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Prognosis of PVOD is worse than PAH. Most patients need lung transplantation. Previous study showed that PVOD patients had higher waitlist mortality compared to PAH patients. To date, there are no study report outcomes of lung transplant in this population. We would like to study the outcome and compare with IPAH patients. <h3>Methods</h3> This is a retrospective observational study. Patients with a diagnosis of PVOD and PAH underwent lung transplant between 2005 and 2018 were identified from SRTR database. Numerical data were reported in mean and standard deviation. Categorical data were reported in count and percent. T-test and Chi-square test were performed to compare variables between 2 groups. Survival was compared using Kaplan-Meier (K-M) method. <h3>Results</h3> 61 PVOD patients and 970 PAH patients underwent lung transplant were identified. There was no significant difference in age and BMI. Patients with PVOD had significant lower post-transplant systolic, diastolic and mean PA pressure and higher cardiac output. LAS at matching were not significantly different. PVOD patients had shorter time on waiting list (152.7±263.34 vs 337.56±511.14, p<0.01). Proportion of patients requiring ECMO post lung transplant were higher in PVOD group (13.11% vs 4.23%, p<0.01). Proportion of patients developing primary graft dysfunction (PGD) were lower in PVOD group (37.5% vs 61.93%, p=0.056). There was no difference of length of stay, FEV1, FVC, PCO2 post lung transplant and acute rejection between 2 groups. Survivals were not different between 2 groups using K-M method (p=0.33). <h3>Conclusion</h3> We found that PVOD patients who underwent lung transplant had shorter waiting time compared to PAH patients which suggest that disease severity of PVOD is higher than PAH. Despite that more PVOD patients required ECMO support post-operative, patient survival and other long-term outcomes such as lung function or rejection were not different between from PAH patients.

Diagnosis of Pulmonary Veno-Occlusive Disease in the Absence of Hemodynamic Abnormalities

<h3>Introduction</h3> Sarcoidosis is a granulomatous disorder of unknown etiology that can lead to pulmonary hypertension (PH). Pulmonary veno-occlusive disease (PVOD) is a subset of PH characterized by intimal proliferation and obliteration of the intralobular veins. We present this case of a patient with sarcoidosis, who had symptoms and imaging consistent with PVOD, which preceded hemodynamic manifestations. <h3>Case Report</h3> A 52-year-old male nonsmoker presented with progressive shortness of breath, dry cough, and mild wheezing over the preceding seven months. He had no hypoxemia. He had a history of neurosarcoidosis, diagnosed nine years prior, for which he was in remission and off all immunosuppression. Physical examination was pertinent only for minimal lower extremity edema. Spirometry, diffusing capacity, 6-minute-walk-test, B-type Natriuretic Peptide (BNP), sarcoid markers, and infectious workup were normal. Chest computed tomography (CT) scan revealed interlobular septal thickening, ground glass opacities (GGOs), and lymphadenopathy, concerning for PVOD. Transthoracic echo (TTE) was normal. His right heart catheterization (RHC) was notable for a mean pulmonary artery pressure of 28 mmHg, a pulmonary capillary wedge pressure of 15 mmHg, and a pulmonary vascular resistance of 1.71 Woods units. The clinical picture was felt to represent PVOD, with imaging findings preceding hemodynamic changes. He was referred to the lung transplant program. Patient's symptoms rapidly progressed before he could undergo lung biopsy and he developed progressive hypoxemia. He underwent a successful bilateral lung transplant two weeks later. The explanted lung pathology revealed granulomatous PVOD. <h3>Summary</h3> In prior reports of sarcoidosis-associated PVOD, PH was noted on TTE or RHC correlating with symptoms well before diagnosis of PVOD. Additionally, in patients with hemodynamic or biopsy proven diagnoses of PH, the combination of GGOs, interlobular septal thickening, and mediastinal lymphadenopathy is 95% sensitive and 89% specific for PVOD. Our case suggests that CT imaging findings should raise the index of suspicion for PVOD, even in the absence of objective evidence of pulmonary vascular changes on TTE and RHC. In patients with symptoms of dyspnea, progressive hypoxemia, and these imaging findings, delayed evaluation for transplant may miss an opportunity for early intervention.

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Predicting Group II pulmonary hypertension: diagnostic accuracy of the H2FPEF and OPTICS scores in Scotland

ObjectiveGroup II pulmonary hypertension (PH) can be challenging to distinguish from Group I PH without proceeding to right heart catheterisation (RHC). The diagnostic accuracy of the H2FPEF and OPTICS scores...

Risk Stratification in Patients with Pulmonary Arterial Hypertension and Candidates for Lung or Heart-Lung Transplantation

<h3>Purpose</h3> During the 2018 6^th PH World Symposium, it was stated that risk stratification scores may be used for the decision of lung (LT) or heart-lung transplantation (HLT) listing in patients with pulmonary arterial hypertension (PAH). The objective of our study was to evaluate risk assessment tools in a cohort of PAH patients listed for LT or HLT. <h3>Methods</h3> All PAH patients listed for LT or HLT between 01/2006 and 12/2018 were included excepted patients with pulmonary veno-occlusive disease or congenital heart diseases because of the specific indications for transplantation in these subtypes of PAH. At the time of listing, risk stratification was assessed according to the ESC-ERS criteria (invasive French and COMPERA methods) and the REVEAL Lite score. The primary endpoint was overall survival after listing. Secondary outcome measures were mortality on waiting list, post-transplant survival, and cumulative incidence of chronic graft dysfunction. <h3>Results</h3> One hundred and six PAH patients were listed for LT or HLT between 01/2006 and 12/2018. The mean age was 37±12 years (73% females). Proportion of idiopathic/heritable PAH was 88%. Overall survival after listing was 72%, 62% and 58% at 1, 3 and 5 years respectively. It was significantly lower in "high risk" patients according to the French method (p=0.0004), the COMPERA method (p=0.005), and the REVEAL Lite score (p=0.01). The mortality rate on list was higher in the "high risk" patients (from 17% with the French method to 19% with the COMPERA method) and urgent transplantation was more frequently performed. Post-transplant survival was 81%, 71% and 66% at 1, 3 and 5 years respectively. It was significantly lower in "high risk" patients without difference in cumulative incidence of chronic graft dysfunction. <h3>Conclusion</h3> PAH patients classified as "high risk" at the time of listing for LT or HLT have poorer outcomes. Time for listing should be anticipated and "high risk" patients should be prioritized to reduce waiting list mortality and improve post-transplant outcomes.

Mechanical Circulatory Support in Lung Transplant Recipients: Early and Long-Term Survival

<h3>Purpose</h3> Lung transplantation can be performed off-pump with sequential one-lung ventilation or with mechanical circulatory support (MCS) either by using a cardiopulmonary bypass or veno-venous / veno-arterial extracorporeal membrane oxygenation. Furthermore, MCS might be necessary throughout postoperative course for improving pulmonary function. Here we aimed to investigate early and long-term survival of lung recipients, who are temporarily in need for mechanical circulatory support during lung transplantation and / or after and additionally who did not receive any mechanical circulatory support. <h3>Methods</h3> We performed a retrospective review of patients who underwent lung transplantation at our center between January 2009 and July 2021. We compared 100 days survival as well as five-year survival of lung transplant recipients, who received mechanical circulatory support intra- and postoperatively (group 1, n=14) vs. no mechanical circulatory support (group 2, n=14) or just intraoperatively (group 3, n=69). Survival depicted as Kaplan-Meier-Curves. <h3>Results</h3> Recipients treated with mechanical circulatory support intra- and postoperatively after lung transplantation (n=14), presented with pulmonary artery hypertension (n=5), pulmonary veno-occlusive disease (n=1), idiopathic fibrosis (n=2), Sarcoidosis (n=1) and chronic obstructive pulmonary disease (n=5). 100 days after initial lung transplantation 4 out of 14 patients were alive. Early survival between group 1 and 2 was 38.5% vs. 85.7% (p=0.0073) and as compared to group 3 38.5% vs 90.9% (p<0.0001). Five-year survival was 33.3% in patient group 1 compared to 67.3% in group 3 (p<0.0001) as well as 33.3% vs 64.3% when compared to patient group 2 (p=0.0262). Survival between group 2 and 3 did not differ significantly. <h3>Conclusion</h3> Here we report clearly that patients after lung transplantation who needed intra- and postoperatively mechanical circulatory support have a significantly reduced early as well as long-term survival compared to recipients without any need of mechanical circulatory support or only intraoperatively. Early and long-term survival of lung recipients treated with circulatory support only intraoperatively did not differ when compared to patients without any use of support.

Prospective clinical assessment of patients with pulmonary arterial hypertension switched from bosentan to macitentan (POTENT).

Even though pulmonary arterial hypertension (PAH) remains an incurable disease, the combination of PAH‐specific therapies allowed evolving from symptom‐based strategies to others aiming to move patients to low‐risk conditions. Endothelin‐1 (ET‐1) receptor antagonists emerged as specific‐PAH drugs that can be used in combination with other specific therapies. This work aimed to perform a prospective clinical assessment of patients with PAH that switched from bosentan to macitentan (POTENT), due to inadequate response. POTENT is a prospective, open‐label, single‐arm, uncontrolled study including PAH patients from our ongoing SAUDIPH registry. It enrolled 50 PAH patients divided as follows: idiopathic/heritable pulmonary arterial hypertension (I/HPAH); n = 24; PAH associated with congenital heart disease, n = 19; PAH associated with connective tissue diseases, n = 5; and pulmonary veno‐occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH), n = 2. At baseline, most patients were in World Health Organization Functional Class (WHO FC) II/III (52.0%). After switching to macitentan, patients were more likely to be in WHO FC I/II (78%) and 22% of the overall cohort moved to a lower risk condition, with three low risk stratification parameters. Mean 6‐min walking distance increased about 34 m after 12 months, with a significant mean change over time (12.63 ± 11.69 at month 3 vs. 40.75 ± 12.57 at month 12, p = 0.002). Most haemodynamic parameters decreased over time, with corresponding negative mean changes (p < 0.001). The safety of macitentan was confirmed by the absence of anaemia and liver injury; clinical worsening was observed only in a small group of patients. In general, macitentan might be a valid alternative to bosentan in PAH stable patients on combination therapy with insufficient clinical response, and presenting intermediate and high‐risk parameters. We anticipate that studying this strategy in PAH subgroups would further clarify its potential and limitations.

Pulmonary Capillary Hemangiomatosis and Refractory Hypoxemia During PH Therapy

<h3>Introduction</h3> Pulmonary capillary hemangiomatosis (PCH), a rare cause of pulmonary hypertension (PH), presents clinically with right heart dysfunction and may be indistinguishable from typical pulmonary arterial hypertension. Vasodilator therapy exacerbates hypoxemia in PCH despite improvement in heart failure symptoms. Lung transplant is the only definitive therapy. We present the case of a patient succumbing to progressive hypoxemia on PH therapy during lung transplant evaluation. Autopsy revealed PCH. <h3>Case Report</h3> A 42-year-old female with PH due to undifferentiated connective tissue disease presented with acute respiratory distress. She was diagnosed 2 years prior and initially treated with macitentan, tadalafil and diuretics with clinical improvement; however, worsening shortness of breath and new finding of hypoxemia developed after 1 year. Imaging revealed faint patchy nodular opacities initially attributed to UCTD-associated pneumonitis. Steroids and mycophenolate failed to achieve radiographic improvement. Repeat right heart catheterization showed continued elevation in pulmonary artery pressure and stably reduced cardiac output. Subcutaneous infusion of Treprostinil was initiated 2 months prior to admission, which worsened hypoxemia. Clinical diagnosis of pulmonary veno-occlusive disease (PVOD) vs PCH was suspected and lung transplant evaluation initiated. On admission, patient presented with syncope and was found to have refractory hypoxemia despite high-flow oxygen supplementation. Cardiogenic shock and hypoxemic respiratory failure ensued, resulting in hepatic and renal failure, leading to cardiac arrest and unsuccessful resuscitation. Autopsy showed PCH. <h3>Summary</h3> Refractory hypoxemia during up-titration of vasodilator therapy for PH should prompt clinical suspicion for atypical causes of PH such as PCH. Early lung transplant referral is essential if PCH/PVOD is suspected given its poor prognosis and potentially harmful responses associated with traditional PH therapy.

Dual-energy CT lung perfusion characteristics in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH): preliminary experience in 63 patients.

In the stratification of potential causes of PH, current guidelines recommend performing V/Q lung scintigraphy to screen for CTEPH. The recognition of CTEPH is based on the identification of lung segments or sub-segments without perfusion but preserved ventilation. The presence of mismatched perfusion defects has also been described in a small proportion of idiopathic pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH). Dual-energy CT lung perfusion changes have not been specifically investigated in these two entities. To compare dual-energy CT (DECT) perfusion characteristics in PAH and PVOD/PCH, with specific interest in PE-type perfusion defects. Sixty-three patients with idiopathic or heritable PAH (group A; n = 51) and PVOD/PCH (group B; n = 12) were investigated with DECT angiography with reconstruction of morphologic and perfusion images. The number of patients with abnormal perfusion did not differ between group A (35/51; 68.6%) and group B (6/12; 50%) (p = 0.31) nor did the mean number of segments with abnormal perfusion per patient (group A: 17.9 ± 4.9; group B: 18.3 ± 4.1; p = 0.91). The most frequent finding was the presence of patchy defects in group A (15/35; 42.9%) and a variable association of perfusion abnormalities in group B (4/6; 66.7%). The median percentage of segments with PE-type defects per patient was significantly higher in group B than in group A (p = 0.041). Two types of PE-type defects were depicted in 8 patients (group A: 5/51; 9.8%; group B: 3/12; 25%), superimposed on PH-related lung abnormalities (7/8) or normal lung (1/8). The iodine concentration was significantly lower in patients with abnormal perfusion (p < 0.001) but did not differ between groups. Perfusion abnormalities did not differ between the two groups at the exception of a higher median percentage of segments with PE-type defects in patients with PVOD/PCH. • Patchy perfusion defect was the most frequent pattern in PAH. • A variable association of perfusion abnormalities was seen in PVOD/PCH. • Lobular and PE-type perfusion defects larger than a sub-segment were depicted in both PAH and PVOD/PCH patients.