Search

The leading cause of premature death in patients with Marfan's syndrome (MS) is type A aortic dissection or rupture due to progressive aortic root dilation. The aim of this study was to analyze aortic root growth in 113 men and 108 women with MS. All patients were prospectively followed with serial echocardiograms of the native aortic root. At baseline, women had on average a 5-mm smaller aortic root diameter adjusted for age than men. Average aortic root growth was 0.42 mm/year (SE 0.05) in men and 0.38 mm/year (SE 0.04) in women. On the basis of aortic root growth rates, the men and women could be divided into 2 normally distributed subgroups: fast and slow growers. Approximately 1 in 7 men (1.5 mm/year, SE 0.5) and approximately 1 in 9 women (1.8 mm/year, SE 0.3) had fast-growing aortic root diameters. Significantly more type A dissections (25% vs 4%, p <0.001) were observed in fast growers than in slow growers; this was found in men and women. Type A dissections were observed in 4 men and 9 women. By reducing the cut-off value by 5 mm for elective aortic root replacement in women, type A dissections could have been prevented in 3 women. In conclusion, guidelines should take gender differences into account, and therefore, the investigators propose reducing the threshold for elective aortic root replacement in women with MS by 5 mm. [ABSTRACT FROM AUTHOR]

Background Clinical monitoring of pulmonary edema due to vascular hyperpermeability in ARDS poses significant clinical challenges. Presently, no biological or radiological markers are available for quantifying pulmonary edema. Our aim was to phenotype pulmonary edema and pulmonary vascular permeability in patients with COVID-19 ARDS. Methods Transpulmonary thermodilution measurements were conducted in 65 COVID-19 ARDS patients on the day of intubation to determine extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPi). In parallel, ventilatory parameters, clinical outcomes, the volume of lung opacity measured by chest CT, and plasma proteomics (358 unique proteins) were compared between tertiles based on the EVLWi and PVPi. Regression models were used to associate EVLWi and PVPi with plasma, radiological, and clinical parameters. Computational pathway analysis was performed on significant plasma proteins in the regression models. Results Patients with the highest EVLWi values at intubation exhibited poorer oxygenation parameters and more days on the ventilator. Extravascular lung water strongly correlated with the total volume of opacity observed on CT(r=0.72), while the PVPi had weaker associations with clinical and radiological parameters. Plasma protein concentrations demonstrated a stronger correlation with PVPi than with EVLWi. The highest tertile of PVPi was associated with proteins linked to the acute phase response (cytokine and chemokine signaling) and extracellular matrix turnover. Conclusions In the clinical setting of COVID-19 ARDS, pulmonary edema (EVLWi) can be accurately quantified through chest CT and parallels deterioration in ventilatory parameters and clinical outcomes. Vascular permeability (PVPi) is strongly reflected by inflammatory plasma proteins.

Introduction: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic BMPR2 variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension., Methods: 28 unaffected carriers (44±16 years, 57% female) and 21 healthy controls (44±18 years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging, transthoracic echocardiography, cardiopulmonary exercise testing and right heart catheterisation. Right ventricular pressure-volume loops were constructed to assess load-independent contractility and compared with a healthy control group. A transgenic Bmpr2 Δ71Ex1/+ rat model was employed to validate findings from humans., Results: Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m -2 versus 62.7±15.3 mL·m -2 ; p=0.001), end-systolic (34.2±10.5 mL·m -2 versus 27.1±8.3 mL·m -2 ; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m -2 versus 58.5±10.7 mL·m -2 ; p=0.007) volumes than control subjects. Bmpr2 Δ71Ex1/+ rats were also observed to have smaller cardiac volumes than wild-type rats. Pressure-volume loop analysis showed that unaffected carriers had significantly higher afterload (arterial elastance 0.15±0.06  versus 0.27±0.08 mmHg·mL -1 ; p<0.001) and end-systolic elastance (0.28±0.07  versus 0.35±0.10 mmHg·mL -1 ; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03 versus 1.36±0.37; p=0.006). During the 4-year follow-up period, two unaffected carriers developed pulmonary arterial hypertension, with normal N-terminal pro-brain natriuretic peptide and transthoracic echocardiography indices at diagnosis., Conclusion: Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2 Δ71Ex1/+ transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods., Competing Interests: Conflicts of interest: F. Perros reports grants from French National Research Agency (ANR-20-CE14-0006) and INSERM (International Research Project (IRP) (Paris – Porto Pulmonary Hypertension Collaborative Laboratory (3PH)). D. Montani reports grants from Janssen, MSD and Acceleron; consultation fees from Janssen, MSD, Ferrer and Acceleron; and payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD. A. Vonk Nordegraaf reports research grants from Janssen, MSD and Ferrer. L. Zhao reports grants from British Heart Foundation (PG/18/2/33446 and BHF RE/18/4/34215). F.S. de Man reports support for the present study from Royal Netherlands Academy of Sciences (CVON-2017-10 Dolphin-Genesis); grants from Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, Netherlands Organisation for Health Research and Development, The Netherlands Organisation for Scientific Research (NWO-VICI: 918.16.610, NWO-VIDI: 917.18.338), Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA and CVON-2018-29 PHAEDRA-IMPACT) and Dutch Heart Foundation (Post doc Dekker 2018T05). H-J. Bogaard reports support for the present study from Royal Netherlands Academy of Sciences (CVON-2017-10 Dolphin-Genesis); grants from MSD, Ferrer, Janssen, Dutch Federation of University Medical Centres, Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA and CVON-2018-29 PHAEDRA-IMPACT). The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is often diagnosed late in acute pulmonary embolism survivors: more efficient testing to expedite diagnosis may considerably improve patient outcomes. The InShape II algorithm safely rules out CTEPH (failure rate 0.29%) while requiring echocardiography in only 19% of patients but may be improved by adding detailed reading of the computed tomography pulmonary angiography diagnosing the index pulmonary embolism., Methods: We evaluated 12 new algorithms, incorporating the CTEPH prediction score, ECG reading, N‑terminal pro-brain natriuretic peptide levels and dedicated computed tomography pulmonary angiography reading, in the international InShape II cohort (n=341) and part of the German FOCUS cohort (n=171). Evaluation criteria included failure rate, defined as the incidence of confirmed CTEPH in pulmonary embolism patients in whom echocardiography was deemed unnecessary by the algorithm, and the overall net reclassification index compared to the InShape II algorithm., Results: The algorithm starting with computed tomography pulmonary angiography reading of the index pulmonary embolism for six signs of CTEPH, followed by ECG/N-terminal pro-brain natriuretic peptide level assessment and echocardiography resulted in the most beneficial change compared to InShape II, with a need for echocardiography in 20% (+5%), a failure rate of 0% and a net reclassification index of +3.5%, reflecting improved performance over the InShape II algorithm. In the FOCUS cohort, this approach lowered echocardiography need to 24% (-6%) and missed no CTEPH cases, with a net reclassification index of +6.0%., Conclusion: Dedicated computed tomography pulmonary angiography reading of the index pulmonary embolism improved the performance of the InShape II algorithm and may improve the selection of pulmonary embolism survivors who require echocardiography to rule out CTEPH., Competing Interests: Conflict of interest: S. Barco received research support from Boston Scientific, Medtronic, Concept Medical, Sanofi and Novartis, all outside this manuscript. M. Delcroix received consulting 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, all outside the submitted work. L. Jara-Palomares reports grants from Daichii, Rovi, GlaxoSmithKline, BMS, Leo Pharma, MSD and Johnson and Johnson. H. Vliegen received grants from Johnson and Johnson; payment or honoraria for lectures, presentations, manuscript writing or educational events from Novartis and Boehringer Ingelheim; and participates on a data safety monitoring board or advisory board for Amarin and Daiichi Sankyo. S.V. Konstantinides reports grants or contacts from Daiichi Sankyo; consulting fees from Boston Scientific, Inari Medical, Bayer AG, Penumbra Inc. and Daiichi Sankyo; and payment or honoraria for lectures, presentations, manuscript writing or educational events from Boston Scientific and Penumbra Inc., all outside of the submitted work. F.A. Klok received research support from Bayer, BMS, BSCI, AstraZeneca, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Foundation, The Dutch Heart Foundation and the Horizon Europe Program, all outside this manuscript. The remaining authors declare no competing interests., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC., Methods: This single-arm, phase-II trial enrolled operable T3-4N0-2 patients with NSCLC without oncogenic drivers. Primary study endpoints were safety, major pathological response (MPR) and pCR. Treatment encompassed platinum-doublet concurrent CRT, IPI 1 mg/kg intravenous and NIVO 360 mg intravenous on day-1, followed by chemotherapy plus NIVO 360 mg 3 weeks later. Thoracic radiotherapy was 50 or 60 Gy, in once-daily doses of 2 Gy. Resections were 6 weeks post-radiotherapy., Results: In a total of 30 patients in the intention-to-treat (ITT) population, grades 3-4 treatment-related adverse events (TRAEs) occurred in 70%, one TRAE grade 5 late-onset pneumonitis on day 96 post-surgery (1/30, 3.3%) occurred, and one non-TRAE COVID-19 death (1/30, 3.3%). pCR and MPR were achieved in 50% (15/30) and 63% (19/30) of the ITT; and in 58% (15/26) and 73% (19/26) of the 26 patients who underwent surgery, respectively. Postoperative melanoma was seen in one non-pCR patient. The R0 rate was 100% (26/26), and no patient failed surgery due to TRAEs. In peripheral blood, proliferative CD8 + T cells were increased, while proliferative regulatory T cells (Tregs) were not. On-treatment, pCR-positives had higher CD8 + CD39 + T cells and lower HLA-DR + Tregs., Conclusions: Neoadjuvant IPI-NIVO-CRT in T3-4N0-2 NSCLC showed acceptable safety with pCR and MPR in 58% and 73% of operated patients, respectively. No patient failed surgery due to TRAEs., Trial Registration Number: NCT04245514., Competing Interests: Competing interests: The authors have disclosed the following conflicts of interest: DEO-L received grants from Janssen and Curium, honoraria from EANM, EAU, ESMO, and Curium, travel support from EANM, ESMO, EAU, and Bayer, and serves on a Bayer advisory board. CD received institutional fees for advisory roles with BMS, AstraZeneca, and MSD. SMSH has research contracts with several pharmaceutical companies and received honoraria from Janssen. IB’s institution received support from BMS, AstraZeneca, and Boehringer Ingelheim, and he received honoraria from AstraZeneca, MSD, and BMS. FLS received a research grant from ViewRay and honoraria from AstraZeneca. SS’s institution received grants from Varian, ViewRay, and AstraZeneca; he received consulting fees and honoraria from AstraZeneca and MSD, and serves on advisory boards for AstraZeneca and MSD. TDdG’s institution received grants from Idera Pharmaceuticals, consulting fees from LAVA Therapeutics and Mendus, and she holds stock in LAVA Therapeutics. All other authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Approximately 80% of patients with non-familial pulmonary arterial hypertension (PAH) lack identifiable pathogenic genetic variants. While most genetic studies of PAH have focused on predicted loss-of-function variants, recent approaches have identified ultra-rare missense variants associated with the disease. FOXF1 encodes a highly conserved transcription factor, essential for angiogenesis and vasculogenesis in human and mouse lungs., Objectives: We identified a rare FOXF1 missense coding variant in two unrelated probands with PAH. FOXF1 is an evolutionarily conserved transcription factor required for lung vascular development and vascular integrity. Our aims were to determine the frequency of FOXF1 variants in larger PAH cohorts compared to the general population, study FOXF1 expression in explanted lung tissue from PAH patients versus control (failed-donor) lungs, and define potential downstream targets linked to PAH development., Methods: Three independent, international, multicenter cohorts were analyzed to evaluate the frequency of FOXF1 rare variants. Various composite prediction models assessed the deleteriousness of individual variants. Bulk RNA sequencing datasets from human explanted lung tissues were compared to failed-donor controls to determine FOXF1 expression. Bioinformatic tools identified putative FOXF1 binding targets, which were orthogonally validated using mouse ChIP-seq datasets., Measurements and Main Results: Seven novel or ultra-rare missense coding variants were identified across three patient cohorts in different regions of the FOXF1 gene, including the DNA binding domain. FOXF1 expression was dysregulated in PAH lungs, correlating with disease severity. Histological analysis showed heterogeneous FOXF1 expression, with the lowest levels in phenotypically abnormal endothelial cells within complex vascular lesions in PAH samples. A hybrid bioinformatic approach identified FOXF1 downstream targets potentially involved in PAH pathogenesis, including BMPR2 ., Conclusions: Large genomic and transcriptomic datasets suggest that decreased FOXF1 expression or predicted dysfunction is associated with PAH.

Background: The clinical phenotype of patients with idiopathic pulmonary arterial hypertension (IPAH) has changed. Whether subgroups of patients with IPAH have different vascular phenotypes is a subject of debate., Research Question: What are the histologic patterns and their clinical correlates in patients with a diagnosis of IPAH or hereditary pulmonary arterial hypertension?, Study Design and Methods: In this this cross-sectional registry study, lung histology of 50 patients with IPAH was assessed qualitatively by two experienced pathologists. In addition, quantitative analysis by means of histopathologic morphometry using immunohistochemistry was performed. Histopathologic characteristics were correlated with clinical and hemodynamic parameters., Results: In this cohort of 50 patients with IPAH, a plexiform vasculopathy was observed in 26 of 50 patients (52%), whereas 24 of 50 patients (48%) showed a nonplexiform vasculopathy. The nonplexiform vasculopathy was characterized by prominent pulmonary microvascular (arterioles and venules) remodeling and vascular rarefaction. Although hemodynamic parameters were comparable in plexiform vs nonplexiform vasculopathy, patients with nonplexiform vasculopathy were older, more often were male, more often had a history of cigarette smoking, and had lower diffusing capacity of the lungs for carbon monoxide at diagnosis. No mutations in established pulmonary arterial hypertension genes were found in the nonplexiform group., Interpretation: This study revealed different vascular phenotypes within the current spectrum of patients with a diagnosis of IPAH, separated by clinical characteristics (age, sex, history of cigarette smoking, and diffusing capacity of the lungs for carbon monoxide at diagnosis). Potential differences in underlying pathobiological mechanisms between patients with plexiform and nonplexiform microvascular disease should be taken into account in future research strategies unravelling the pathophysiologic features of pulmonary hypertension and developing biology-targeted treatment approaches., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: E. J. N., H. J. B., and A. V. N. have received speaker fees for lectures and educational events from Janssen, MSD, and United Therapeutics/Ferrer. E. J. N. has received consulting fees from Janssen and United Therapeutics/Ferrer. A. V. N. has received consulting fees from Janssen, MSD, and United Therapeutics/Ferrer. None declared (J. A. S., C. S., L. J. M., A. B., J. A., F. S. D. M., T. R., P. D.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Long-term changes in exercise capacity and cardiopulmonary hemodynamics after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have been poorly described., Methods: We analyzed the data from 2 prospective surgical CTEPH cohorts in Hammersmith Hospital, London, and Amsterdam UMC. A structured multimodal follow-up was adopted, consisting of right heart catheterization, cardiac magnetic resonance imaging, and cardiopulmonary exercise testing before and after PEA. Preoperative predictors of residual pulmonary hypertension (PH; mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥2 WU) and long-term exercise intolerance (VO 2 max <80%) at 18 months were analyzed., Results: A total of 118 patients (61 from London and 57 from Amsterdam) were included in the analysis. Both cohorts displayed a significant improvement of pulmonary hemodynamics, right ventricular (RV) function, and exercise capacity 6 months after PEA. Between 6 and 18 months after PEA, there were no further improvements in hemodynamics and RV function, but the proportion of patients with impaired exercise capacity was high and slightly increased over time (52%-59% from 6 to 18 months). Long-term exercise intolerance was common and associated with preoperative diffusion capacity for carbon monoxide (DLCO), preoperative mixed venous oxygen saturation, and postoperative PH and right ventricular ejection fraction (RVEF). Clinically significant RV deterioration (RVEF decline >3%; 5 [9%] of 57 patients) and recurrent PH (5 [14%] of 36 patients) rarely occurred beyond 6 months after PEA. Age and preoperative DLCO were predictors of residual PH post-PEA., Conclusions: Restoration in exercise tolerance, cardiopulmonary hemodynamics, and RV function occurs within 6 months. No substantial changes occurred between 6 and 18 months after PEA in the Amsterdam cohort. Nevertheless, long-term exercise intolerance is common and associated with postoperative RV function., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The 2022 European Society of Cardiology/European Respiratory Society pulmonary hypertension (PH) guidelines incorporate cardiac magnetic resonance (CMR) imaging metrics in the risk stratification of patients with pulmonary arterial hypertension (PAH). Thresholds to identify patients at estimated 1-year mortality risks of < 5%, 5% to 20%, and > 20% are introduced. However, these cutoff values are mostly single center-based and require external validation., Research Question: What are the discriminative prognostic properties of the current CMR risk thresholds stratifying patients with PAH?, Study Design and Methods: We analyzed data from incident, treatment-naïve patients with PAH from the Amsterdam University Medical Centres, Vrije Universiteit, The Netherlands. The discriminative properties of the proposed CMR three risk strata were tested at baseline and first reassessment, using the following PH guideline variables: right ventricular ejection fraction, indexed right ventricular end-systolic volume, and indexed left ventricular stroke volume., Results: A total of 258 patients with PAH diagnosed between 2001 and 2022 fulfilled the study criteria and were included in this study. Of these, 172 had follow-up CMR imaging after 3 months to 1.5 years. According to the CMR three risk strata, most patients were classified at intermediate risk (n = 115 [45%]) upon diagnosis. Only 29 (11%) of patients with PAH were classified at low risk, and 114 (44%) were classified at high risk. Poor survival discrimination was seen between risk groups. Appropriate survival discrimination was seen at first reassessment., Interpretation: Risk stratifying patients with PAH with the recent proposed CMR cutoffs from the European Society of Cardiology/European Respiratory Society 2022 PH guidelines requires adjustment because post-processing consensus is lacking and general applicability is limited. Risk assessment at follow-up yielded better survival discrimination, emphasizing the importance of the individual treatment response., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: H. J. B. and A. V. N. were supported by research grants from Actelion, GSK, and Ferrer (Therabel). None declared (L. R. C., J. N. W., J. T. M., L. J. M., F. S. d. M.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

COVID-19-related acute respiratory distress syndrome (ARDS) can lead to long-term pulmonary fibrotic lesions. Alveolar fibroproliferative response (FPR) is a key factor in the development of pulmonary fibrosis. N-terminal peptide of procollagen III (NT-PCP-III) is a validated biomarker for activated FPR in ARDS. This study aimed to assess the association between dynamic changes in alveolar FPR and long-term outcomes, as well as mortality in COVID-19 ARDS patients. We conducted a prospective cohort study of 154 COVID-19 ARDS patients. We collected bronchoalveolar lavage (BAL) and blood samples for measurement of 17 pulmonary fibrosis biomarkers, including NT-PCP-III. We assessed pulmonary function and chest computed tomography (CT) at 3 and 12 mo after hospital discharge. We performed joint modeling to assess the association between longitudinal changes in biomarker levels and mortality at day 90 after starting mechanical ventilation. 154 patients with 284 BAL samples were analyzed. Of all patients, 40% survived to day 90, of whom 54 completed the follow-up procedure. A longitudinal increase in NT-PCP-III was associated with increased mortality (HR 2.89, 95% CI: 2.55-3.28; P < 0.001). Forced vital capacity and diffusion for carbon monoxide were impaired at 3 mo but improved significantly at one year after hospital discharge ( P = 0.03 and P = 0.004, respectively). There was no strong evidence linking alveolar FPR during hospitalization and signs of pulmonary fibrosis in pulmonary function or chest CT images during 1-yr follow-up. In COVID-19 ARDS patients, alveolar FPR during hospitalization was associated with higher mortality but not with the presence of long-term fibrotic lung sequelae within survivors. NEW & NOTEWORTHY This is the first prospective study on the longitudinal alveolar fibroproliferative response in COVID-19 ARDS and its relationship with mortality and long-term follow-up. We used the largest cohort of COVID-19 ARDS patients who had consecutive bronchoalveolar lavages and measured 17 pulmonary fibroproliferative biomarkers. We found that a higher fibroproliferative response during admission was associated with increased mortality, but not correlated with long-term fibrotic lung sequelae in survivors.

Objective: A 45% threshold of right ventricular ejection fraction (RVEF) is proposed clinically relevant in patients with pulmonary arterial hypertension (PAH). We aim to determine treatment response, long-term right ventricular (RV) functional stability and prognosis of patients with PAH reaching or maintaining the RVEF 45% threshold., Methods: Incident, treatment-naive, adult PAH patients with cardiac magnetic resonance imaging at baseline and first follow-up were included (total N=127) and followed until date of censoring or death/lung transplantation. Patients were categorised into two groups based on 45% RVEF. Baseline predictors, treatment response and prognosis were assessed with logistic regression analyses, two-way analysis of variance and log-rank tests., Results: Patients were 50±17 years old, 73% female, of which N=75 reached or maintained the 45% RVEF threshold at follow-up (RVEF≥45%@FU), while N=52 patients did not (RVEF<45%@FU). RV end-diastolic volume and N-terminal pro-B-type natriuretic peptide at baseline were multivariable predictors of an RVEF ≥45% at follow-up. A 40% pulmonary vascular resistance (PVR) reduction resulted in greater improvement in RV function (ΔRVEF 17±11 vs. 5±8; p interaction <0.001) compared to a PVR reduction <40%, but did not guarantee an RVEF ≥45%. Finally, the 45% RVEF threshold was associated with stable RV function during long-term follow-up and better survival (HR: 1.91 (95% CI: 1.11 to 3.27)). Patients failing to reach or maintain the 45% RVEF threshold at first follow-up mostly stayed below this threshold over the next consecutive visits., Conclusion: After treatment initiation, 60% of patients with PAH reach or maintain the 45% RVEF threshold, which is associated with a long-term stable RV function and favourable prognosis., Competing Interests: Competing interests: HJB and AVN were supported by research grants from Actelion, GSK and Ferrer (Therabel). The remaining authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with chronic thromboembolic pulmonary hypertension. However, RV mass does not always normalize. It is unknown whether incomplete reversal of RV remodeling results from extracellular matrix expansion (diffuse interstitial fibrosis) or cellular hypertrophy, and whether residual RV remodeling relates to altered diastolic function., Methods: We prospectively included 25 patients with chronic thromboembolic pulmonary hypertension treated with PEA. Structured follow-up measurements were performed before, and 6 and 18 months after PEA. With single beat pressure-volume loop analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV-arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed). The extracellular volume fraction of the RV free wall was measured by cardiac magnetic resonance imaging and used to separate the myocardium into cellular and matrix volume. Circulating collagen biomarkers were analyzed to determine the contribution of collagen metabolism., Results: RV mass significantly decreased from 43±15 to 27±11g/m 2 (-15.9 g/m 2 [95% CI, -21.4 to -10.5]; P <0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m 2 in healthy controls [95% CI, 2.1 to 9.8]; P <0.01). On the contrary, Eed normalized after PEA. Extracellular volume fraction in the right ventricular free wall increased after PEA from 31.0±3.8 to 33.6±3.5% (3.6% [95% CI, 1.2-6.1]; P =0.013) as a result of a larger reduction in cellular volume than in matrix volume ( P interaction =0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-β (transforming growth factor-β) were elevated at baseline and remained elevated post-PEA., Conclusions: Although cellular hypertrophy regresses and diastolic stiffness normalizes after PEA, a relative increase in extracellular volume remains. Incomplete regression of diffuse RV interstitial fibrosis after PEA is accompanied by elevated levels of circulating collagen biomarkers, suggestive of active collagen turnover., Competing Interests: Disclosures All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this article.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. Important advances have enabled better understanding, characterisation, and treatment of this condition. Guidelines recommending systematic follow-up after acute pulmonary embolism, and the insight that CTEPH can mimic acute pulmonary embolism on initial presentation, have led to the definition of CTEPH imaging characteristics, the introduction of artificial intelligence diagnosis pathways, and thus the prospect of easier and earlier CTEPH diagnosis. In this Series paper, we show how the understanding of CTEPH as a sequela of inflammatory thrombosis has driven successful multidisciplinary management that integrates surgical, interventional, and medical treatments. We provide imaging examples of classical major vessel targets, describe microvascular targets, define available tools, and depict an algorithm facilitating the initial treatment strategy in people with newly diagnosed CTEPH based on a multidisciplinary team discussion at a CTEPH centre. Further work is needed to optimise the use and combination of multimodal therapeutic options in CTEPH to improve long-term outcomes for patients., Competing Interests: Declaration of interests MD reports research grants from Janssen; and speaker and consultancy fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Janssen, United Therapeutics, and MSD, outside of the submitted work and all paid to her institution. She is holder of a Janssen Chair for Pulmonary Hypertension at the KU Leuven. MdP reports speaker fees and consultancy honoraria from AstraZeneca and BMS; speaker fees from Bayer; and consultancy honoraria from Merck and Roche. XJ reports research grants from Janssen, MSD, and Bayer HealthCare; and speaker fees from Janssen and MSD, outside of the submitted work. DPJ reports speaker and consultancy fees from Janssen, outside of the submitted work. IML has relationships with drug companies, including AOP-Health, Actelion-Janssen, MSD, United Therapeutics, Pulnovo, Medtronic, Neutrolis and Sanofi; in addition to being an investigator in trials involving these companies, relationships include consultancy service, research grants, and membership of scientific advisory boards. HM reports research grants from Nippon Shinyaku; speaker and consultancy fees from Bayer, Janssen, and MSD; and speaker fees from Kaneka Medix, Mochida, Nippon Shinyaku, and Niprol, outside of the submitted work. LJM participated in an advisory board on CTEPH imaging for Janssen. GS has received advisory board and speaker fees from Acceleron, Bayer, Janssen, MSD, and Merck. CBW reports speaker fees from Actelion/Janssen, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, OrphaCare, and Pfizer; and consultancy honoraria from Actelion/Janssen and MSD. NHK has received 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, outside of the submitted work. RQ declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Precapillary pulmonary hypertension (precPH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness., Objectives: This study aimed to investigate RA function using pressure-volume (PV) loops, isolated cardiomyocyte, and histological analyses., Methods: RA PV loops were constructed in control subjects (n = 9) and precPH patients (n = 27) using magnetic resonance and catheterization data. RA stiffness (pressure rise during atrial filling) and right atrioventricular coupling index (RA minimal volume / RV end-diastolic volume) were compared in a larger cohort of patients with moderate (n = 39) or severe (n = 41) RV diastolic stiffness. Cardiomyocytes were isolated from RA tissue collected from control subjects (n = 6) and precPH patients (n = 9) undergoing surgery. Autopsy material was collected from control subjects (n = 6) and precPH patients (n = 4) to study RA hypertrophy, capillarization, and fibrosis., Results: RA PV loops showed 3 RA cardiac phases (reservoir, passive emptying, and contraction) with dilatation and elevated pressure in precPH. PrecPH patients with severe RV diastolic stiffness had increased RA stiffness and worse right atrioventricular coupling index. Cardiomyocyte cross-sectional area was increased 2- to 3-fold in precPH, but active tension generated by the sarcomeres was unaltered. There was no increase in passive tension of the cardiomyocytes, but end-stage precPH showed reduced number of capillaries per mm 2 accompanied by interstitial and perivascular fibrosis., Conclusions: RA PV loops show increased RA stiffness and suggest atrioventricular uncoupling in patients with severe RV diastolic stiffness. Isolated RA cardiomyocytes of precPH patients are hypertrophied, without intrinsic sarcomeric changes. In end-stage precPH, reduced capillary density is accompanied by interstitial and perivascular fibrosis., Competing Interests: Funding Support and Author Disclosures Drs Bogaard, Vonk Noordegraaf, Goumans, and de Man were supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA, CVON-2018-29 PHAEDRA-IMPACT, and CVON-2017-10 Dolphin-Genesis). Drs Vonk Noordegraaf and de Man were further supported by the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610, NWO-VIDI: 917.18.338). Dr de Man was supported by a Dutch Heart Foundation Dekker senior postdoc grant (2018T059). Drs Bogaard and Vonk Noordegraaf have received research grant support from Actelion, GSK, and Ferrer (Therabel). Dr de Man has received research grant support from Janssen and BIAL. Dr Handoko has received consultancy/speaker fees from Novartis, Boehringer Ingelheim, AstraZeneca, Vifor, Bayer, MSD, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department., Methods: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings., Results: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%)., Conclusions: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department., Trial Registration Number: NTR6163., Competing Interests: Competing interests: All authors have completed and submitted the ICMJE form for Disclosure of Potential Conflicts of Interest. JS reported receipt of an innovation grant of the Amsterdam UMC, location AMC, University of Amsterdam and a grant of Health Care Efficiency Program of the Netherlands Organization for Health Research and Development (ZonMW:843001806). MMNPK reports to have received personal fees from the before-mentioned grants. SM reports to have received grants and personal fees from Bayer, BMS Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Portola, GSK and Aspen. TSRvE reports to have received a personal fee, PhD Scholarship grant, from Amsterdam UMC., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The shape and distribution of vascular lesions in pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH) are different. We investigated whether automated quantification of pulmonary vascular morphology and densitometry in arteries and veins imaged by computed tomographic pulmonary angiography (CTPA) could distinguish PE from CTEPH. We analyzed CTPA images from a cohort of 16 PE patients, 6 CTEPH patients, and 15 controls. Pulmonary vessels were extracted with a graph-cut method, and separated into arteries and veins using deep-learning classification. Vascular morphology was quantified by the slope (α) and intercept (β) of the vessel radii distribution. To quantify lung perfusion defects, the median pulmonary vascular density was calculated. By combining these measurements with densities measured in parenchymal areas, pulmonary trunk, and descending aorta, a static perfusion curve was constructed. All separate quantifications were compared between the three groups. No vascular morphology differences were detected in contrast to vascular density values. The median vascular density (interquartile range) was -567 (113), -452 (95), and -470 (323) HU, for the control, PE, and CTEPH group. The static perfusion curves showed different patterns between groups, with a statistically significant difference in aorta-pulmonary trunk gradient between the PE and CTEPH groups ( p  = 0.008). In this proof of concept study, not vasculature morphology but densities differentiated between patients of three groups. Further technical improvements are needed to allow for accurate differentiation between PE and CTEPH, which in this study was only possible statistically by measuring the density gradient between aorta and pulmonary trunk., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background Pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension improves resting hemodynamics and right ventricular (RV) function. Because exercise tolerance frequently remains impaired, RV function may not have completely normalized after PEA. Therefore, we performed a detailed invasive hemodynamic study to investigate the effect of PEA on RV function during exercise. Methods and Results In this prospective study, all consenting patients with chronic thromboembolic pulmonary hypertension eligible for surgery and able to perform cycle ergometry underwent cardiac magnetic resonance imaging, a maximal cardiopulmonary exercise test, and a submaximal invasive cardiopulmonary exercise test before and 6 months after PEA. Hemodynamic assessment and analysis of RV pressure curves using the single-beat method was used to determine load-independent RV contractility (end systolic elastance), RV afterload (arterial elastance), RV-arterial coupling (end systolic elastance-arterial elastance), and stroke volume both at rest and during exercise. RV rest-to-exercise responses were compared before and after PEA using 2-way repeated-measures analysis of variance with Bonferroni post hoc correction. A total of 19 patients with chronic thromboembolic pulmonary hypertension completed the entire study protocol. Resting hemodynamics improved significantly after PEA. The RV exertional stroke volume response improved 6 months after PEA (79±32 at rest versus 102±28 mL during exercise; P <0.01). Although RV afterload (arterial elastance) increased during exercise, RV contractility (end systolic elastance) did not change during exercise either before (0.43 [0.32-0.58] mm Hg/mL versus 0.45 [0.22-0.65] mm Hg/mL; P =0.6) or after PEA (0.32 [0.23-0.40] mm Hg/mL versus 0.28 [0.19-0.44] mm Hg/mL; P =0.7). In addition, mean pulmonary artery pressure-cardiac output and end systolic elastance-arterial elastance slopes remained unchanged after PEA. Conclusions The exertional RV stroke volume response improves significantly after PEA for chronic thromboembolic pulmonary hypertension despite a persistently abnormal afterload and absence of an RV contractile reserve. This may suggest that at mildly elevated pulmonary pressures, stroke volume is less dependent on RV contractility and afterload and is primarily determined by venous return and conduit function.

Background: Exact benefits of currently recommended close monitoring in intermediate high risk acute pulmonary embolism (PE) patients are unknown., Methods: This prospective observational cohort study determined clinical characteristics, and disease course of intermediate high risk acute PE patients in an academic hospital setting . Frequency of hemodynamic deterioration, use of rescue reperfusion therapy and PE related mortality, were outcomes of interest., Results: Of 98 intermediate high risk PE patients included for analysis, 81 patients (83%) were closely monitored. Two deteriorated hemodynamically and were treated with rescue reperfusion therapy. One patient survived after this., Conclusions: In these 98 intermediate high risk PE patients, hemodynamic deterioration occurred in three patients and rescue reperfusion therapy of two closely monitored patients led to survival of one. Underlining the need for better recognition of patients benefitting from and research in the optimal way of close monitoring.

Background: The idiopathic pulmonary arterial hypertension (iPAH) phenotype is changing from a predominantly young female patient to an older, frequently obese patient of either sex. Many newly diagnosed iPAH-patients have risk factors for left ventricular diastolic dysfunction (LVDD), possibly affecting management and treatment., Aim: To determine whether the H 2 FPEF-score identifies a subgroup of iPAH-patients with blunted response to PAH-targeted treatment., Study Design and Methods: We performed a retrospective analysis of 253 treatment-naïve iPAH-patients (1989-2019) with a confirmed diagnosis after right heart catheterization by a multidisciplinary team. Follow-up RHC measurements were available in 150 iPAH-patients. iPAH-patients were stratified by the H 2 FPEF-score; a score ≥5 identified a higher possibility of (concealed) LVDD., Results: The presence of a high H 2 FPEF-score in incident iPAH-patients rose 30% in thirty years. Patients with a H 2 FPEF-score ≥5 were older, more often male and/or obese, and had more comorbidities than patients with a H 2 FPEF-score ≤1. A high H 2 FPEF-score was associated with worse survival and poor functional capacity. Right ventricular function was equally depressed among iPAH-groups. Imaging and invasive hemodynamic measurements suggested concealed LVDD in iPAH patients with a high H 2 FPEF-score. At follow-up, hemodynamic and functional responses were similar in iPAH-patients with a high or low H 2 FPEF-score., Conclusions: While a high H 2 FPEF-score in iPAH is associated with a worse prognosis and signs of LVDD, hemodynamic and functional responses to PAH treatment are not predicted by the H 2 FPEF-score., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Positron emission tomography (PET) is a promising technique to improve the assessment of systemic sclerosis associated interstitial lung disease (SSc-ILD). This technique could be of particular value in patients with severe diffuse cutaneous SSc (dcSSc) that are possibly eligible for autologous hematopoietic stem cell transplantation (aHSCT). aHSCT is a potentially effective therapy for patients with severe dcSSc and ILD, leading to stabilization or improvement of lung function. However, there is a high need to improve patient selection, which includes (1) the selection of patients with rapidly progressive ILD for early rather than last-resort aHSCT (2) the prediction of treatment response on ILD and (3) the understanding of the mechanism(s) of action of aHSCT in the lungs. As previous studies with 18 F-FDG PET in SSc-ILD and other forms of ILD have demonstrated its potential value in predicting disease progression and reactivity to anti-inflammatory treatment, we discuss the potential benefit of using this technique in patients with early severe dcSSc and ILD in the context of aHSCT. In addition, we discuss the potential value of other PET tracers in the assessment of ILD and understanding the mechanisms of action of aHSCT in the lung. Finally, we provide several suggestions for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Broens, van der Laken, Zwezerijnen, Nossent, Meijboom, Spierings, de Vries-Bouwstra, van Laar and Voskuyl.)

Background: Pulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA-RV interaction., Methods: PAH patients with low or high end-diastolic elastance (E ed ) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying-RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure., Results: With increased E ed , RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high E ed , resulting in higher vena cava backflow. Upon treatment, E ed was reduced in ~50% of the patients with high E ed , which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom E ed remained high., Conclusions: In PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline E ed , diastolic stiffness remained high, despite treatment. A reduction in E ed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow., Competing Interests: Conflict of interest: J.N. Wessels has nothing to disclose. Conflict of interest: S.A. Mouratoglou has nothing to disclose. Conflict of interest: J. van Wezenbeek has nothing to disclose. Conflict of interest: M.L. Handoko has nothing to disclose. Conflict of interest: J.T. Marcus has nothing to disclose. Conflict of interest: L.J. Meijboom has nothing to disclose. Conflict of interest: B.E. Westerhof has nothing to disclose. Conflict of interest: H.J. Bogaard was supported by research grants from Actelion, GSK and Ferrer (Therabel). Conflict of interest: G.J. Strijkers has nothing to disclose. Conflict of interest: A. Vonk Noordegraaf was supported by research grants from Actelion, GSK and Ferrer (Therabel). Conflict of interest: F.S. de Man has nothing to disclose., (Copyright ©The authors 2022.)

Background: The success of pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) is usually evaluated by performing a right heart catheterisation (RHC). Here, we investigate whether residual pulmonary hypertension (PH) can be sufficiently excluded without the need for a RHC, by making use of early post-operative haemodynamics, or N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiopulmonary exercise testing (CPET) and transthoracic echocardiography (TTE) 6 months after PEA., Methods: In an observational analysis, residual PH after PEA measured by RHC was related to haemodynamic data from the post-operative intensive care unit time and data from a 6-month follow-up assessment including NT-proBNP, TTE and CPET. After dichotomisation and univariate analysis, sensitivity, specificity, positive predictive value, negative predictive value (NPV) and likelihood ratios were calculated., Results: Thirty-six out of 92 included patients had residual PH 6 months after PEA (39%). Correlation between early post-operative and 6-month follow-up mean pulmonary artery pressure was moderate (Spearman rho 0.465, p<0.001). Early haemodynamics did not predict late success. NT-proBNP >300 ng·L -1 had insufficient NPV (0.71) to exclude residual PH. Probability for PH on TTE had a moderate NPV (0.74) for residual PH. Peak oxygen consumption ( V ' O 2 ) <80% predicted had the highest sensitivity (0.85) and NPV (0.84) for residual PH., Conclusions: CPET 6 months after PEA, and to a lesser extent TTE, can be used to exclude residual CTEPH, thereby safely reducing the number of patients needing to undergo re-RHC after PEA., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2022.)

Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. A larger volume at a given pressure generates more wall tension. Return of reflected waves early after the onset of contraction, when RV volume is larger, may augment RV load. We aimed to elucidate: (1) the distribution of arrival times of peak reflected waves in treatment-naïve PAH patients; (2) the relationship between time of arrival of reflected waves and RV morphology; and (3) the effect of PAH treatment on the arrival time of reflected waves. Wave separation analysis was conducted in 68 treatment-naïve PAH patients. In the treatment-naïve condition, 54% of patients had mid-systolic return of reflected waves (defined as 34-66% of systole). Despite similar pulmonary vascular resistance (PVR), patients with mid-systolic return had more pronounced RV hypertrophy compared to those with late-systolic or diastolic return (RV mass/body surface area; mid-systolic return 54.6 ± 12.6 g m -2 , late-systolic return 44.4 ± 10.1 g m -2 , diastolic return 42.8 ± 13.1 g m -2 ). Out of 68 patients, 43 patients were further examined after initial treatment. At follow-up, the stiffness of the proximal arteries, given as characteristic impedance, decreased from 0.12 to 0.08 mmHg s mL -1 . Wave speed was attenuated from 13.3 to 9.1 m s -1 , and the return of reflected waves was delayed from 64% to 71% of systole. In conclusion, reflected waves arrive at variable times in PAH. Early return of reflected waves was associated with more RV hypertrophy. PAH treatment not only decreased PVR, but also delayed the timing of reflected waves. KEY POINTS: Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. Larger volume at a given pressure causes larger RV wall tension. Early return of reflected waves adds RV pressure in early systole, when RV volume is relatively large. Thus, early return of reflected waves may increase RV wall tension. Wave reflection can provide a description of RV load. In PAH, reflected waves arrive back at variable times. In over half of PAH patients, the RV is exposed to mid-systolic return of reflected waves. Mid-systolic return of reflected waves is related to RV hypertrophy. PAH treatment acts favourably on the RV not only by reducing resistance, but also by delaying the return of reflected waves. Arrival timing of reflected waves is an important parameter for understanding the relationship between RV load and its function in PAH., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Objectives: Closer reading of computed tomography pulmonary angiography (CTPA) scans of patients presenting with acute pulmonary embolism (PE) may identify those at high risk of developing chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to validate the predictive value of six radiological predictors that were previously proposed., Methods: Three hundred forty-one patients with acute PE were prospectively followed for development of CTEPH in six European hospitals. Index CTPAs were analysed post hoc by expert chest radiologists blinded to the final diagnosis. The accuracy of the predictors using a predefined threshold for 'high risk' (≥ 3 predictors) and the expert overall judgment on the presence of CTEPH were assessed., Results: CTEPH was confirmed in nine patients (2.6%) during 2-year follow-up. Any sign of chronic thrombi was already present in 74/341 patients (22%) on the index CTPA, which was associated with CTEPH (OR 7.8, 95%CI 1.9-32); 37 patients (11%) had ≥ 3 of 6 radiological predictors, of whom 4 (11%) were diagnosed with CTEPH (sensitivity 44%, 95%CI 14-79; specificity 90%, 95%CI 86-93). Expert judgment raised suspicion of CTEPH in 27 patients, which was confirmed in 8 (30%; sensitivity 89%, 95%CI 52-100; specificity 94%, 95%CI 91-97)., Conclusions: The presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future CTEPH diagnosis, comparable to overall expert judgment, while the latter was associated with higher sensitivity. Dedicated CTPA reading for signs of CTEPH may therefore help in early detection of CTEPH after PE, although in our cohort this strategy would not have detected all cases., Key Points: • Three expert chest radiologists re-assessed CTPA scans performed at the moment of acute pulmonary embolism diagnosis and observed a high prevalence of chronic thrombi and signs of pulmonary hypertension. • On these index scans, the presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), comparable to overall expert judgment. • Dedicated CTPA reading for signs of CTEPH may help in early detection of CTEPH after acute pulmonary embolism., (© 2021. The Author(s).)

Background: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages., Methods: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49)., Results: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAH-patients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females ≤45years had best prognosis in comparison to females ≥55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females ≤45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females ≤45years had an event at a later time point, RV function was more impaired at end-stage disease., Conclusions: Sex hormones are differently associated with RV function in male and female PAH-patients. DHEA-S appeared to be lower in male and female PAH-patients. Females ≤45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and ventricular (RV) dysfunction are frequently observed. The question remains whether the PH with the associated RV/RA dysfunction in HFpEF are markers of disease severity., Methods: To obtain insight in the relative importance of pressure-overload and left-to-right interaction, we compared RA and RV function in 3 groups: 1. HFpEF (n=13); 2. HFpEF-PH (n=33), and; 3. pulmonary arterial hypertension (PAH) matched to pulmonary artery pressures of HFpEF-PH (PH limited to mPAP ≥30 and ≤50 mmHg) (n=47). Patients underwent right heart catheterization and cardiac magnetic resonance imaging., Results: The right ventricle in HFpEF-PH was less dilated and hypertrophied than in PAH. In addition, RV ejection fraction was more preserved (HFpEF-PH: 52±11 versus PAH: 36±12%). RV filling patterns differed: vena cava backflow during RA contraction was observed in PAH only. In HFpEF-PH, RA pressure was elevated throughout the cardiac cycle (HFpEF-PH: 10 [8-14] versus PAH: 7 [5-10] mm Hg), while RA volume was smaller, reflecting excessive RA stiffness (HFpEF-PH: 0.14 [0.10-0.17] versus PAH: 0.08 [0.06-0.11] mm Hg/mL). RA stiffness was associated with an increased eccentricity index (HFpEF-PH: 1.3±0.2 versus PAH: 1.2±0.1) and interatrial pressure gradient (9 [5 to 12] versus 2 [-2 to 5] mm Hg)., Conclusions: RV/RA function was less compromised in HFpEF-PH than in PAH, despite similar pressure-overload. Increased RA pressure and stiffness in HFpEF-PH were explained by left atrial/RA-interaction. Therefore, our results indicate that increased RA pressure is not a sign of overt RV failure but rather a reflection of HFpEF-severity.

Introduction: The pulmonary arterial morphology of patients with pulmonary embolism (PE) is diverse and it is unclear how the different vascular lesions evolve after initiation of anticoagulant treatment. A better understanding of the evolution of computed tomography pulmonary angiography (CTPA) findings after the start of anticoagulant treatment may help to better identify those PE patients prone to develop chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the evolution of various thromboembolic lesions on CTPA over time after the initiation of adequate anticoagulant treatment in individual acute PE patients with and without an ultimate diagnosis of CTEPH., Methods: We analysed CTPA at diagnosis of acute PE (baseline) and at follow-up in 41 patients with CTEPH and 124 patients without an ultimate diagnosis of CTEPH, all receiving anticoagulant treatment. Central and segmental pulmonary arteries were scored by expert chest radiologists as normal or affected. Lesions were further subclassified as 1) central thrombus, 2) total thrombotic occlusion, 3) mural thrombus, 4) web or 5) tapered pulmonary artery., Results: Central thrombi resolved after anticoagulant treatment, while mural thrombi and total thrombotic occlusions either resolved or evolved into webs or tapered pulmonary arteries. Only patients with an ultimate diagnosis of CTEPH exhibited webs and tapered pulmonary arteries on the baseline scan. Moreover, such lesions always persisted after follow-up., Conclusions: Webs and tapered pulmonary arteries at the time of PE diagnosis strongly indicate a state of chronic PE and should raise awareness for possible CTEPH, particularly in patients with persistent dyspnoea after anticoagulant treatment for acute PE., Competing Interests: Conflict of interest: G.J.A.M. Boon was supported by the Dutch Heart Foundation (2017T064). Conflict of interest: F.A. Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, MSD and Actelion, the Dutch Heart Foundation (2017T064), the Netherlands Organisation for Health Research and Development, and the Dutch Thrombosis Association. The remaining authors have no conflicts of interest to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

COVID-19 patients have increased risk of pulmonary embolism (PE), but symptoms of both conditions overlap. Because screening algorithms for PE in COVID-19 patients are currently lacking, PE might be underdiagnosed. We evaluated a screening algorithm in which all patients presenting to the ED with suspected or confirmed COVID-19 routinely undergo D-dimer testing, followed by CT pulmonary angiography (CTPA) if D-dimer is ≥ 1.00 mg/L. Consecutive adult patients presenting to the ED of two university hospitals in Amsterdam, The Netherlands, between 01-10-2020 and 31-12-2020, who had a final diagnosis of COVID-19, were retrospectively included. D-dimer and CTPA results were obtained. Of 541 patients with a final diagnosis of COVID-19 presenting to the ED, 25 (4.6%) were excluded because D-dimer was missing, and 71 (13.1%) because they used anticoagulation therapy. Of 445 included patients, 185 (41.6%; 95%CI 37.0-46.3) had a D-dimer ≥ 1.00 mg/L. CTPA was performed in 169 of them, which showed PE in 26 (15.4%; 95%CI 10.3-21.7), resulting in an overall detection rate of 5.8% (95%CI 3.9-8.4) in the complete study group. In patients with and without PE at CTPA, median D-dimer was 9.84 (IQR 3.90-29.38) and 1.64 (IQR 1.17-3.01), respectively (p < 0.001). PE prevalence increased with increasing D-dimer, ranging from 1.2% (95%CI 0.0-6.4) if D-dimer was 1.00-1.99 mg/L, to 48.6% (95%CI 31.4-66.0) if D-dimer was ≥ 5.00 mg/L. In conclusion, by applying this screening algorithm, PE was identified in a considerable proportion of COVID-19 patients. Prospective management studies should assess if this algorithm safely rules-out PE if D-dimer is < 1.00 mg/L., (© 2021. The Author(s).)

Background: Expert reading often reveals radiological signs of chronic thromboembolic pulmonary hypertension (CTEPH) or chronic PE on computed tomography pulmonary angiography (CTPA) performed at the time of acute pulmonary embolism (PE) presentation preceding CTEPH. Little is known about the accuracy and reproducibility of CTPA reading by radiologists in training in this setting., Objectives: To evaluate 1) whether signs of CTEPH or chronic PE are routinely reported on CTPA for suspected PE; and 2) whether CTEPH-non-expert readers achieve comparable predictive accuracy to CTEPH-expert radiologists after dedicated instruction., Methods: Original reports of CTPAs demonstrating acute PE in 50 patients whom ultimately developed CTEPH, and those of 50 PE who did not, were screened for documented signs of CTEPH. All scans were re-assessed by three CTEPH-expert readers and two CTEPH-non-expert readers (blinded and independently) for predefined signs and overall presence of CTEPH., Results: Signs of chronic PE were mentioned in the original reports of 14/50 cases (28%), while CTEPH-expert radiologists had recognized 44/50 (88%). Using a standardized definition (≥3 predefined radiological signs), moderate-to-good agreement was reached between CTEPH-non-expert readers and the experts' consensus (k-statistics 0.46; 0.61) at slightly lower sensitivities. The CTEPH-non-expert readers had moderate agreement on the presence of CTEPH (κ-statistic 0.38), but both correctly identified most cases (80% and 88%, respectively)., Conclusions: Concomitant signs of CTEPH were poorly documented in daily practice, while most CTEPH patients were identified by CTEPH-non-expert readers after dedicated instruction. These findings underline the feasibility of achieving earlier CTEPH diagnosis by assessing CTPAs more attentively., (Copyright © 2021. Published by Elsevier B.V.)

Purpose of Review: In the past decades, the diagnostic and therapeutic management of chronic thromboembolic pulmonary hypertension (CTEPH) has been revolutionized., Recent Findings: Advances in epidemiological knowledge and follow-up studies of pulmonary embolism patients have provided more insight in the incidence and prevalence. Improved diagnostic imaging techniques allow accurate assessment of the location and extend of the thromboembolic burden in the pulmonary artery tree, which is important for the determination of the optimal treatment strategy. Next to the pulmonary endarterectomy, the newly introduced technique percutaneous pulmonary balloon angioplasty and/or P(A)H-targeted medical therapy has been shown to be beneficial in selected patients with CTEPH and might also be of importance in patients with chronic thromboembolic pulmonary vascular disease., Summary: In this era of a comprehensive approach to CTEPH with different treatment modalities, a multidisciplinary approach guides management decisions leading to optimal treatment and follow-up of patients with CTEPH., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We defined the frequency of respiratory community-acquired bacterial co-infection in patients with COVID-19, i.e. patients with a positive SARS-CoV-2 PCR or a COVID-19 Reporting and Data System (CO-RADS) score ≥ 4, based on a complete clinical assessment, including prior antibiotic use, clinical characteristics, inflammatory markers, chest computed tomography (CT) results and microbiological test results., Methods: Our retrospective study was conducted within a cohort of prospectively included patients admitted for COVID-19 in our tertiary medical centres between 1-3-2020 and 1-6-2020. A multidisciplinary study team developed a diagnostic protocol to retrospectively categorize patients as unlikely, possible or probable bacterial co-infection based on clinical, radiological and microbiological parameters in the first 72 h of admission. Within the three categories, we summarized patient characteristics and antibiotic consumption., Results: Among 281 included COVID-19 patients, bacterial co-infection was classified as unlikely in 233 patients (82.9%), possible in 35 patients (12.4%) and probable in 3 patients (1.1%). Ten patients (3.6%) could not be classified due to inconclusive data. Within 72 h of hospital admission, 81% of the total study population and 78% of patients classified as unlikely bacterial co-infection received antibiotics., Conclusions: COVID-19 patients are unlikely to have a respiratory community-acquired bacterial co-infection. This study underpins recommendations for restrictive use of antibacterial drugs in patients with COVID-19., (© 2021. The Author(s).)

For young adults with end-stage idiopathic pulmonary hypertension, a valved graft connecting the central pulmonary artery to the distal aortic arch can provide substantial palliation of symptoms and may defer lung transplantation https://bit.ly/2TvMFFC., Competing Interests: Conflict of interest: P. Symersky has nothing to disclose. Conflict of interest: S.M.A. Jansen has nothing to disclose. Conflict of interest: S.K. Kamminga has nothing to disclose. Conflict of interest: L.J. Meijboom has nothing to disclose. Conflict of interest: E.J. Lust has nothing to disclose. Conflict of interest: P. Eghtesady has nothing to disclose. Conflict of interest: R.M. Grady has nothing to disclose. Conflict of interest: H.J. Bogaard has nothing to disclose., (Copyright ©The authors 2021.)

Background: The Post-Pulmonary Embolism Syndrome (PPES) comprises heterogeneous entities, including chronic thromboembolic disease with/without pulmonary hypertension (CTEPH/CTEPD), and deconditioning., Objectives: To assess underlying physiological determinants of PPES, and efficacy and safety of rehabilitation training in these patients., Methods: 56 consecutive PE patients with persistent dyspnea and/or functional limitations despite ≥3 months of anticoagulation underwent standardized diagnostic work-up including exercise testing as part of routine practice. All diagnostic (imaging and cardiopulmonary function) tests were interpreted by a core group of experienced clinicians. A subgroup of patients without CTEPH or other treatable conditions was referred for a 12-week personalized rehabilitation program, studying changes in physical condition and patient-reported outcome measures., Results: Persistent vascular occlusions were observed in 21/56 patients (38%) and CTEPH was confirmed in ten (18%). Regarding those without CTEPH, impaired cardiopulmonary responses were evident in 18/39 patients with available CPET data (46%), unrelated to chronic thrombi. Rehabilitation was completed by 27 patients after excluding 29 (patients with CTEPH or treatable comorbidities, refusal, ineligibility, or training elsewhere). Training intensity, PE-specific quality of life (PEmb-QoL) and fatigue (CIS) improved with a median difference of 20 W (p = 0.001), 3.9 points (p < 0.001) and 16 points (p = 0.003), respectively. Functional status (Post-VTE Functional Status Scale) improved ≥1 grade in 18 (67%) patients, and declined in one (3.7%)., Conclusions: Our findings suggest that abnormal cardiopulmonary responses to exercise are common in patients with PPES and are not limited to those with chronic thrombi. Offering pulmonary rehabilitation to patients not treated otherwise seems safe and promising., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Evidence from previous studies comparing lung ultrasound to thoracic computed tomography (CT) in intensive care unit (ICU) patients is limited due to multiple methodologic weaknesses. While addressing methodologic weaknesses of previous studies, the primary aim of this study is to investigate the diagnostic accuracy of lung ultrasound in a tertiary ICU population., Methods: This is a single-center, prospective diagnostic accuracy study conducted at a tertiary ICU in the Netherlands. Critically ill patients undergoing thoracic CT for any clinical indication were included. Patients were excluded if time between the index and reference test was over eight hours. Index test and reference test consisted of 6-zone lung ultrasound and thoracic CT, respectively. Hemithoraces were classified by the index and reference test as follows: consolidation, interstitial syndrome, pneumothorax and pleural effusion. Sensitivity, specificity, positive and negative likelihood ratio were estimated., Results: In total, 87 patients were included of which eight exceeded the time limit and were subsequently excluded. In total, there were 147 respiratory conditions in 79 patients. The estimated sensitivity and specificity to detect consolidation were 0.76 (95%CI: 0.68 to 0.82) and 0.92 (0.87 to 0.96), respectively. For interstitial syndrome they were 0.60 (95%CI: 0.48 to 0.71) and 0.69 (95%CI: 0.58 to 0.79). For pneumothorax they were 0.59 (95%CI: 0.33 to 0.82) and 0.97 (95%CI: 0.93 to 0.99). For pleural effusion they were 0.85 (95%CI: 0.77 to 0.91) and 0.77 (95%CI: 0.62 to 0.88)., Conclusions: In conclusion, lung ultrasound is an adequate diagnostic modality in a tertiary ICU population to detect consolidations, interstitial syndrome, pneumothorax and pleural effusion. Moreover, one should be careful not to interpret lung ultrasound results in deterministic fashion as multiple respiratory conditions can be present in one patient. Trial registration This study was retrospectively registered at Netherlands Trial Register on March 17, 2021, with registration number NL9344., (© 2021. The Author(s).)

Background: Diagnostic delay of chronic thromboembolic pulmonary hypertension (CTEPH) exceeds 1 year, contributing to higher mortality. Health economic consequences of late CTEPH diagnosis are unknown. We aimed to develop a model for quantifying the impact of diagnosing CTEPH earlier on survival, quality-adjusted life-years (QALYs) and healthcare costs., Material and Methods: A Markov model was developed to estimate lifelong outcomes, depending on the degree of delay. Data on survival and quality of life were obtained from published literature. Hospital costs were assessed from patient records (n=498) at the Amsterdam UMC - VUmc, which is a Dutch CTEPH referral center. Medication costs were based on a mix of standard medication regimens., Results: For 63-year-old CTEPH patients with a 14-month diagnostic delay of CTEPH (median age and delay of patients in the European CTEPH Registry), lifelong healthcare costs were estimated at EUR 117 100 for a mix of treatment options. In a hypothetical scenario of maximal reduction of current delay, improved survival was estimated at a gain of 3.01 life-years and 2.04 QALYs. The associated cost increase was EUR 44 654, of which 87% was due to prolonged medication use. This accounts for an incremental cost-utility ratio of EUR 21 900/QALY., Conclusion: Our constructed model based on the Dutch healthcare setting demonstrates a substantial health gain when CTEPH is diagnosed earlier. According to Dutch health economic standards, additional costs remain below the deemed acceptable limit of EUR 50 000/QALY for the particular disease burden. This model can be used for evaluating cost-effectiveness of diagnostic strategies aimed at reducing the diagnostic delay., Competing Interests: Conflict of interest: G.J.A.M. Boon reports grants from the Dutch Heart Foundation and Actelion Pharmaceuticals Ltd outside the submitted work. Conflict of interest: W.B. van den Hout reports grants from the Netherlands Organisation for Health Research and Development (ZonMw) and National Health Care Institute (Zorginstituut Nederland) outside the submitted work. Conflict of interest: S. Barco has nothing to disclose. Conflict of interest: H.J. Bogaard has nothing to disclose. Conflict of interest: M. Delcroix has nothing to disclose. Conflict of interest: M.V. Huisman reports grants from the ZonMW Dutch Healthcare Fund, grants and personal fees from Pfizer–BMS, Bayer Health Care and Daiichi-Sankyo, and grants from Leo Pharma, outside the submitted work. Conflict of interest: S.V. Konstantinides has nothing to disclose. Conflict of interest: L.J. Meijboom has nothing to disclose. Conflict of interest: E.J. Nossent has nothing to disclose. Conflict of interest: P. Symersky has nothing to disclose. Conflict of interest: A. Vonk Noordegraaf reports grants from the Netherlands CardioVascular Research Initiative and Netherlands Organization for Scientific Research, other support from Johnson & Johnson and Ferrer in the past 3 years, and nonfinancial support as a member of a scientific advisory board of Morphogen-XI, outside the submitted work. Conflict of interest: F.A. Klok reports grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, MSD, Actelion, the Netherlands Thrombosis Foundation and the Dutch Heart Foundation outside the submitted work., (Copyright ©The authors 2021.)

Background and Objective: Patients with coronavirus disease 2019 (COVID-19) pneumonia present with typical findings on chest computed tomography (CT), but the underlying histopathological patterns are unknown. Through direct regional correlation of imaging findings to histopathological patterns, this study aimed to explain typical COVID-19 CT patterns at tissue level., Methods: Eight autopsy cases were prospectively selected of patients with PCR-proven COVID-19 pneumonia with varying clinical manifestations and causes of death. All had been subjected to chest CT imaging 24-72 h prior to death. Twenty-seven lung areas with typical COVID-19 patterns and two radiologically unaffected pulmonary areas were correlated to histopathological findings in the same lung regions., Results: Two dominant radiological patterns were observed: ground-glass opacity (GGO) (n = 11) and consolidation (n = 16). In seven of 11 sampled areas of GGO, diffuse alveolar damage (DAD) was observed. In four areas of GGO, the histological pattern was vascular damage and thrombosis, with (n = 2) or without DAD (n = 2). DAD was also observed in five of 16 samples derived from areas of radiological consolidation. Seven areas of consolidation were based on a combination of DAD, vascular damage and thrombosis. In four areas of consolidation, bronchopneumonia was found. Unexpectedly, in samples from radiologically unaffected lung parenchyma, evidence was found of vascular damage and thrombosis., Conclusion: In COVID-19, radiological findings of GGO and consolidation are mostly explained by DAD or a combination of DAD and vascular damage plus thrombosis. However, the different typical CT patterns in COVID-19 are not related to specific histopathological patterns. Microvascular damage and thrombosis are even encountered in the radiologically normal lung., (© 2021 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Respiratory gating is generally recommended in 4D flow MRI of the heart to avoid blurring and motion artifacts. Recently, a novel automated contact-less camera-based respiratory motion sensor has been introduced., Purpose: To compare camera-based respiratory gating (CAM) with liver-lung-navigator-based gating (NAV) and no gating (NO) for whole-heart 4D flow MRI., Study Type: Retrospective., Subjects: Thirty two patients with a spectrum of cardiovascular diseases., Field Strength/sequence: A 3T, 3D-cine spoiled-gradient-echo-T1-weighted-sequence with flow-encoding in three spatial directions., Assessment: Respiratory phases were derived and compared against each other by cross-correlation. Three radiologists/cardiologist scored images reconstructed with camera-based, navigator-based, and no respiratory gating with a 4-point Likert scale (qualitative analysis). Quantitative image quality analysis, in form of signal-to-noise ratio (SNR) and liver-lung-edge (LLE) for sharpness and quantitative flow analysis of the valves were performed semi-automatically., Statistical Tests: One-way repeated measured analysis of variance (ANOVA) with Wilks's lambda testing and follow-up pairwise comparisons. Significance level of P ≤ 0.05. Krippendorff's-alpha-test for inter-rater reliability., Results: The respiratory signal analysis revealed that CAM and NAV phases were highly correlated (C = 0.93 ± 0.09, P < 0.01). Image scoring showed poor inter-rater reliability and no significant differences were observed (P ≥ 0.16). The image quality comparison showed that NAV and CAM were superior to NO with higher SNR (P = 0.02) and smaller LLE (P < 0.01). The quantitative flow analysis showed significant differences between the three respiratory-gated reconstructions in the tricuspid and pulmonary valves (P ≤ 0.05), but not in the mitral and aortic valves (P > 0.05). Pairwise comparisons showed that reconstructions without respiratory gating were different in flow measurements to either CAM or NAV or both, but no differences were found between CAM and NAV reconstructions., Data Conclusion: Camera-based respiratory gating performed as well as conventional liver-lung-navigator-based respiratory gating. Quantitative image quality analysis showed that both techniques were equivalent and superior to no-gating-reconstructions. Quantitative flow analysis revealed local flow differences (tricuspid/pulmonary valves) in images of no-gating-reconstructions, but no differences were found between images reconstructed with camera-based and navigator-based respiratory gating., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) are both associated with right ventricular (RV) failure and mortality. However, CTEPH patients are older, more often male and usually have more co-morbidities than iPAH patients, including a history of venous thromboembolism. Therefore, RV adaptation to pressure-overload in CTEPH may be different than in iPAH., Methods: We included all treatment-naive CTEPH and iPAH patients diagnosed in the Amsterdam UMC between 2000 and 2019 if cardiac magnetic resonance imaging (CMR) and a right heart catheterization were performed at time of diagnosis. Load-dependent RV volumes and mass were assessed with CMR. Load-independent RV contractility, afterload and diastolic stiffness in relation to afterload were obtained using single beat pressure-volume loop analysis. Differences in RV characteristics between CTEPH and iPAH were analyzed using multiple linear regression with interaction testing after correcting for confounders., Results: We included 235 patients in this study and performed pressure-volume loop analysis in 136 patients. In addition to being older and more often male, CTEPH patients had a lower pulmonary vascular resistance than iPAH patients at the time of diagnosis. After correcting for these confounders, CTEPH patients had a somewhat higher RV end-diastolic volume index (87 ± 27 ml vs 82 ± 25 ml; p < .01), and a lower RV relative wall thickness (0.6 ± 0,1 g/ml vs 0.7 ± 0,2 g/ml; p < .01). The correlation coefficient of RV diastolic stiffness to afterload was higher in CTEPH compared to iPAH (p < .05; independent of age and gender)., Conclusions: Despite differences in patient characteristics, disease etiology and physiology, RV functional parameters in CTEPH and iPAH are mostly similar. The right ventricle in CTEPH is marginally more dilated, stiffer and less hypertrophic than in iPAH., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited., Objectives: To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome., Methods: Paired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured., Measurements and Main Results: In all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined., Conclusions: Critically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory "storm" in severe COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nossent, Schuurman, Reijnders, Saris, Jongerius, Blok, de Vries, Duitman, Vonk Noordegraaf, Meijboom, Lutter, Heunks, Bogaard and van der Poll.)

Background: Treatment of patients with pulmonary arterial hypertension (PAH) is conventionally based on functional plus invasive measurements obtained during right heart catheterization (RHC). Whether risk assessment during repeated measurements could also be performed on the basis of imaging parameters is unclear, as a direct comparison of strategies is lacking., Research Question: How does the predictive value of noninvasive parameters compare with that of invasive hemodynamic measurements 1 year after the diagnosis of idiopathic PAH?, Study Design and Methods: One hundred and eighteen patients with idiopathic PAH who underwent RHC and cardiac MRI (CMR) were included in this study (median time between baseline evaluation and first parameter measures, 1.0 [0.8-1.2] years). Forty-four patients died or underwent lung transplantation. Forward Cox regression analyses were done to determine the best predictive functional, hemodynamic, and/or imaging model. Patients were classified as high risk if the event occurred < 5 years after diagnosis (n = 24), whereas patients without event were classified as low risk., Results: A prognostic model based on age, sex, and absolute values at follow-up of functional parameters (6-min walk distance) performed well (Akaike information criterion [AIC], 279; concordance, 0.67). Predictive models with only hemodynamic (right atrial pressure, mixed venous oxygen saturation; AIC, 322; concordance, 0.66) or imaging parameters (right ventricular ejection fraction; AIC, 331; concordance, 0.63) at 1 year of follow-up performed similarly. The predictive value improved when functional data were combined with either hemodynamic data (AIC, 268; concordance, 0.69) or imaging data (AIC, 273; concordance, 0.70). A model composed of functional, hemodynamic, and imaging data performed only marginally better (AIC, 266; concordance, 0.69). Finally, changes between baseline and 1-year follow-up were observed for multiple hemodynamic and CMR parameters; only a change in CMR parameters was of prognostic predictive value., Interpretation: At 1 year of follow-up, risk assessment based on CMR is at least equal to risk assessment based on RHC. In this study, only changes in CMR, but not hemodynamic parameters, were of prognostic predictive value during the first year of follow-up., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lung ultrasound can adequately monitor disease severity in pneumonia and acute respiratory distress syndrome. We hypothesize lung ultrasound can adequately monitor COVID-19 pneumonia in critically ill patients., Methods: Adult patients with COVID-19 pneumonia admitted to the intensive care unit of two academic hospitals who underwent a 12-zone lung ultrasound and a chest CT examination were included. Baseline characteristics, and outcomes including composite endpoint death or ICU stay > 30 days were recorded. Lung ultrasound and CT images were quantified as a lung ultrasound score involvement index (LUSI) and CT severity involvement index (CTSI). Primary outcome was the correlation, agreement, and concordance between LUSI and CTSI. Secondary outcome was the association of LUSI and CTSI with the composite endpoints., Results: We included 55 ultrasound examinations in 34 patients, which were 88% were male, with a mean age of 63 years and mean P/F ratio of 151. The correlation between LUSI and CTSI was strong (r = 0.795), with an overall 15% bias, and limits of agreement ranging - 40 to 9.7. Concordance between changes in sequentially measured LUSI and CTSI was 81%. In the univariate model, high involvement on LUSI and CTSI were associated with a composite endpoint. In the multivariate model, LUSI was the only remaining independent predictor., Conclusions: Lung ultrasound can be used as an alternative for chest CT in monitoring COVID-19 pneumonia in critically ill patients as it can quantify pulmonary involvement, register changes over the course of the disease, and predict death or ICU stay > 30 days., Trial Registration: NTR, NL8584. Registered 01 May 2020-retrospectively registered, https://www.trialregister.nl/trial/8584.

Pulmonary vascular resistance (PVR) and compliance are comparable in proximal and distal chronic thromboembolic pulmonary hypertension (CTEPH). However, proximal CTEPH is associated with inferior right ventricular (RV) adaptation. Early wave reflection in proximal CTEPH may be responsible for altered RV function. The aims of the study are as follows: 1 ) to investigate whether reflected pressure returns sooner in proximal than in distal CTEPH and 2 ) to elucidate whether the timing of reflected pressure is related to RV dimensions, ejection fraction (RVEF), hypertrophy, and wall stress. Right heart catheterization and cardiac MRI were performed in 17 patients with proximal CTEPH and 17 patients with distal CTEPH. In addition to the determination of PVR, compliance, and characteristic impedance, wave separation analysis was performed to determine the magnitude and timing of the peak reflected pressure (as %systole). Findings were related to RV dimensions and time-resolved RV wall stress. Proximal CTEPH was characterized by higher RV volumes, mass, and wall stress, and lower RVEF. While PVR, compliance, and characteristic impedance were similar, proximal CTEPH was related to an earlier return of reflected pressure than distal CTEPH (proximal 53 ± 8% vs. distal 63 ± 15%, P < 0.05). The magnitude of the reflected pressure waves did not differ. RV volumes, RVEF, RV mass, and wall stress were all related to the timing of peak reflected pressure. Poor RV function in patients with proximal CTEPH is related to an early return of reflected pressure wave. PVR, compliance, and characteristic impedance do not explain the differences in RV function between proximal and distal CTEPH. NEW & NOTEWORTHY In chronic thromboembolic pulmonary hypertension (CTEPH), proximal localization of vessel obstructions is associated with poor right ventricular (RV) function compared with distal localization, though pulmonary vascular resistance, vascular compliance, characteristic impedance, and the magnitude of wave reflection are similar. In proximal CTEPH, the RV is exposed to an earlier return of the reflected wave. Early wave reflection may increase RV wall stress and compromise RV function.

Residual pulmonary hypertension is an important sequela after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Recurrent thrombosis or embolism could be a contributor to this residual pulmonary hypertension but the potential extent of its role is unknown in part because data on incidence are lacking. We aimed to analyze the incidence of new intravascular abnormalities after pulmonary endarterectomy and determine hemodynamic and functional implications. A total of 33 chronic thromboembolic pulmonary hypertension patients underwent routine CT pulmonary angiography before and six months after pulmonary endarterectomy, together with right heart catheterization and exercise testing. New vascular lesions were defined as (1) a normal pulmonary artery before pulmonary endarterectomy and containing a thrombus, web, or early tapering six months after pulmonary endarterectomy or (2) a pulmonary artery already containing thrombus, web, or early tapering at baseline, but increasing six months after pulmonary endarterectomy. Nine of 33 (27%) chronic thromboembolic pulmonary hypertension patients showed new vascular lesions on CT pulmonary angiography six months after pulmonary endarterectomy. In a subgroup of patients undergoing CT pulmonary angiography 18 months after pulmonary endarterectomy, no further changes in lesions were noted. Hemodynamic and functional outcomes were not different between patients with and without new vascular lesions. New vascular lesions are common after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension; currently their origin, dynamics, and long-term consequences remain unknown., Competing Interests: The author(s) declare that there is no conflict of interest. R.J.L. reports personal fees from BTG and Philips outside the submitted work. A.V.N. reports grant support from Actelion, GlaxoSmithKline, Bayer, and Pfizer outside the submitted work. H.-J.B. reports grant support from Actelion, GlaxoSmithKline, Therabel, Pfizer, and Bayer outside the submitted work., (© The Author(s) 2020.)

OBJECTIVE. The purpose of this study is to assess CT-based markers predictive of the development of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism. MATERIALS AND METHODS. Identified from a search of local registries, 48 patients who had CTEPH develop were included in the study group, and 113 patients who had complete resolution of acute pulmonary embolism were included in the control group. Baseline CT scans obtained at the time of the initial pulmonary embolism event were evaluated for the degree of clot-induced vessel obstruction, the quantitative Walsh score, the ratio of the right ventricle diameter to the left ventricle diameter, the right atrium diameter, the pulmonary artery diameter, right heart thrombus, pericardial effusion, lung infarction, and mosaic attenuation. Classification and regression tree analysis was used to create a decision tree. The decision tree was externally validated on an anonymized cohort of 50 control subjects and 50 patients with CTEPH. RESULTS. During univariable analysis, an increase in the degree occlusive clot on initial imaging, a decrease in the Walsh score, absence of pericardial effusion, presence of lung infarction, and the presence of mosaic attenuation were associated with an increased probability of CTEPH development. In the final decision tree, the occlusive nature of the clot remained. Two patients in the cohort used for external validation had nondiagnostic findings and were excluded. The decision process correctly classified 33% (16/48) of patients who had CTEPH develop and 86% (43/50) of patients who did not have CTEPH develop, for an odds ratio of 3.1 (95% CI, 1.1-8.3). CONCLUSION. The presence of an occlusive clot on initial imaging is associated with an increased probability of CTEPH development. Presence of mosaic attenuation and lung infarction may also predict CTEPH development, although additional studies are needed.

Background: The likelihood of a tumor recurrence in patients with T3-4N0-1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28-38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019-003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence., Methods/design: This single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0-1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020. On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery on distribution and phenotype of peripheral blood immune subsets., Discussion: The INCREASE trial will evaluate the safety and local efficacy of a combination of 4 modalities in patients with resectable, T3-4N0-1 NSCLC. Translational research will investigate the mechanisms of action and drug related adverse events., Trial Registration: Netherlands Trial Registration (NTR): NL8435 , Registered 03 March 2020.