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 (VO2max <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. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Nailfold capillary density is lower in patients with pulmonary arterial hypertension (PAH). It is unclear whether this observation signifies a unique systemic manifestation of PAH, or reflects microcirculatory dysfunction secondary to pulmonary hypertension (PH). Capillary density and loop dimensions were measured by nailfold-capillaroscopy (NC) in 30 PAH (23 idiopathic, or iPAH, 7 hereditary, or hPAH), 17 chronic thromboembolic PH (CTEPH) patients and 48 controls. NC-Measurements were repeated after pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) in CTEPH patients. We examined whether NC-measurements were related to markers of disease severity and predictive of time to clinical worsening (TTCW) as tested by univariate linear/logistic regression and cox-regression analysis, respectively. Capillary density was significantly lower in PAH (7.5 ± 1.1, p < 0.001) and in CTEPH (8.4 ± 1.5, p < 0.001) compared to asymptomatic controls (10.3 ± 1.0 capillaries/mm). Capillary density was similar in iPAH and hPAH and unrelated to hemodynamics in either PAH or CTEPH. A lower capillary density was predictive of clinical worsening in PAH (p 0.05). After normalization of pulmonary artery pressures by PEA or BPA, capillary density remained reduced in CTEPH patients. Capillary loop apex, capillary and venous- and arterial limb diameter were increased in patients with PAH and CTEPH compared to controls. Nailfold capillary density is reduced to a similar extent in iPAH, hPAH and CTEPH. Normalization of hemodynamics by PEA or BPA does not lead to a restoration of capillary density in CTEPH. Capillary dimensions were increased in both patients with PAH and CTEPH. Lower capillary density was predictive of clinical worsening in PAH. Our findings indicate that a loss of peripheral capillaries is not specific to PAH and is not related to the hemodynamic disturbance per se, but that shared mechanisms may account for a simultaneous development of a systemic microangiopathy and pulmonary vascular remodeling.

Journal of Gastroenterology and HepatologyEarly View Letter to the Editor Impact of self-reported ancestry on the epidemiology of hepatocellular carcinoma E Loon, E Loon [email protected] orcid.org/0009-0003-1011-938X Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USASearch for more papers by this authorC Narvaez-Barbecho, C Narvaez-Barbecho Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USASearch for more papers by this authorJP Ortiz, JP Ortiz Gastroenterología y Hepatología, Centro de Enfermedades Hepáticas y Digestivas, Bogotá, ColombiaSearch for more papers by this authorD Balderramo, D Balderramo Department of Gastroenterology, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, ArgentinaSearch for more papers by this authorE Carrera, E Carrera Department of Gastroenterology and Hepatology, Hospital Eugenio Espejo, Quito, EcuadorSearch for more papers by this authorJ Diaz-Ferrer, J Diaz-Ferrer Department of Gastroenterology, Hospital Nacional Edgardo Rebagliati Martins, Lima, PeruSearch for more papers by this authorM Arrese, M Arrese Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, ChileSearch for more papers by this authorAZ Mattos, AZ Mattos orcid.org/0000-0002-3063-0199 Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, BrazilSearch for more papers by this authorA Boonstra, A Boonstra Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The NetherlandsSearch for more papers by this authorJD Debes, JD Debes Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The NetherlandsSearch for more papers by this author E Loon, E Loon [email protected] orcid.org/0009-0003-1011-938X Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USASearch for more papers by this authorC Narvaez-Barbecho, C Narvaez-Barbecho Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USASearch for more papers by this authorJP Ortiz, JP Ortiz Gastroenterología y Hepatología, Centro de Enfermedades Hepáticas y Digestivas, Bogotá, ColombiaSearch for more papers by this authorD Balderramo, D Balderramo Department of Gastroenterology, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, ArgentinaSearch for more papers by this authorE Carrera, E Carrera Department of Gastroenterology and Hepatology, Hospital Eugenio Espejo, Quito, EcuadorSearch for more papers by this authorJ Diaz-Ferrer, J Diaz-Ferrer Department of Gastroenterology, Hospital Nacional Edgardo Rebagliati Martins, Lima, PeruSearch for more papers by this authorM Arrese, M Arrese Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, ChileSearch for more papers by this authorAZ Mattos, AZ Mattos orcid.org/0000-0002-3063-0199 Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, BrazilSearch for more papers by this authorA Boonstra, A Boonstra Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The NetherlandsSearch for more papers by this authorJD Debes, JD Debes Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The NetherlandsSearch for more papers by this author First published: 13 April 2024 https://doi.org/10.1111/jgh.16578 Declaration of conflict of interest: The contributing authors have no financial, professional, personal, or other conflicts of interest to declare. Ethical approval: Each participating organization provided ethical approval of the study and all study procedures. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Financial support: This study was supported by the European-Latin American ESCALON consortium, funded by the EU Horizon 2020 program, project number 825510 and Foundation for the National Institutes of Health NIH-R21TW012390-01A1. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Tian Y, Wang B. Unraveling the pathogenesis of non-alcoholic fatty liver diseases through genome-wide association studies. J. Gastroenterol. Hepatol. 2023; 38: 1877–1885. https://doi.org/10.1111/jgh.16330 10.1111/jgh.16330 CASPubMedWeb of Science®Google Scholar 2Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatol Baltim Md. 2023; 77: 1335–1347. https://doi.org/10.1097/HEP.0000000000000004 10.1097/HEP.0000000000000004 PubMedWeb of Science®Google Scholar 3Farah M, Anugwom C, Ferrer JD et al. Changing epidemiology of hepatocellular carcinoma in South America: a report from the South American liver research network. Ann. Hepatol. 2023; 28: 100876. https://doi.org/10.1016/j.aohep.2022.100876 10.1016/j.aohep.2022.100876 PubMedWeb of Science®Google Scholar 4Conomos MP, Laurie CA, Stilp AM et al. Genetic diversity and association studies in US Hispanic/Latino populations: applications in the Hispanic Community Health Study/Study of Latinos. Am. J. Hum. Genet. 2016; 98: 165–184. https://doi.org/10.1016/j.ajhg.2015.12.001 10.1016/j.ajhg.2015.12.001 CASPubMedWeb of Science®Google Scholar 5Cavalcante LN, Porto J, Mazo D et al. African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population. Ann. Hepatol. 2022; 27: 100728. https://doi.org/10.1016/j.aohep.2022.100728 10.1016/j.aohep.2022.100728 CASPubMedWeb of Science®Google Scholar 6Debes JD, Boonstra A, Balderramo D et al. Hepatobiliary cancers in South America: disparity strikes. Lancet Gastroenterol. Hepatol. 2019; 4: 581. https://doi.org/10.1016/S2468-1253(19)30188-8 10.1016/S2468-1253(19)30188-8 PubMedWeb of Science®Google Scholar 7Ayoub A, Anugwom CM, Prieto J et al. Assessment of STAT4 variants and risk of hepatocellular carcinoma in Latin Americans and Europeans. Cancer 2023; 15: 4530. https://doi.org/10.3390/cancers15184530 10.3390/cancers15184530 CASGoogle Scholar 8Fu S, Karim D, Prieto J et al. Assessment of TLL1 variant and risk of hepatocellular carcinoma in Latin Americans and Europeans. Ann. Hepatol. 2024; 29: 101181. https://doi.org/10.1016/j.aohep.2023.101181 10.1016/j.aohep.2023.101181 CASPubMedWeb of Science®Google Scholar 9Goble S, Akambase J, Prieto J et al. MBOAT7 rs641738 variant is not associated with an increased risk of hepatocellular carcinoma in a Latin American cohort. Dig. Dis. Sci. 2023; 68: 4212–4220. https://doi.org/10.1007/s10620-023-08104-y 10.1007/s10620-023-08104-y CASPubMedWeb of Science®Google Scholar Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

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.

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: 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.

Background: Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to improvement in right ventricular (RV) function in the majority of chronic thromboembolic pulmonary hypertension (CTEPH) patients. However, little is known about the long-term effects of PEA on RV function. We aimed to describe long-term changes in RV function in PEA treated CTEPH-patients. Methods: In this prospective study we included patients diagnosed with CTEPH who underwent PEA. Structured follow-up measurements were performed using right heart catheterization (RHC) and cardiac magnetic resonance (CMR) imaging before PEA and 6 and 18 months after treatment. Single beat pressure-volume loop analysis was used to determine load-independent RV contractility (Ees) and RV afterload (Ea). RV volume, mass and function were derived from CMR. Results: The study protocol was completed in 25 CTEPH-patients. PEA led to a significant decline in mean pulmonary arterial pressure (mPAP 45±11 to 24±9 mmHg; p<0.0001), pulmonary vascular resistance (PVR 561 [427-711] to 132 [112-194] dynes/s/cm 5 ; p<0.0001) and RV afterload (Ea 0.6 [0.49-0.81] to 0.2 [0.2-0.3] mmHg/ml; p<0.0001) 6 months after treatment. In addition, RV dimensions improved 6 months after PEA as demonstrated by a decrease in indexed RV end-diastolic volume (RVEDVi 91±28 to 71±13 ml/m 2 ; p=0.0009), indexed RV mass (43±15 to 27±11 g/m 2 ; p <0.0001) and increase in RV ejection fraction (RVEF 41±14 to 52±9%; p=0.0003) and Ees (0.7 [0.5-1.1] to 0.3 [0.2-0.4] mmHg/ml; p<0.0001). No further changes were seen in pulmonary hemodynamics and RV dimensions between 6 and 18 months after PEA. Conclusion: Restoration in pulmonary hemodynamics and RV dimensions occurs within 6 months after PEA. No further improvements are observed between 6 and 18 months after PEA.

Rationale: Pulmonary hypertension encompasses progressive disorders leading to right ventricular dysfunction and early death. Late detection is an important cause of poor clinical outcomes. However, biomarkers that accurately predict the presence of pulmonary hypertension are currently lacking. Objectives: In this study, we provide evidence that blood platelets contain a distinctive ribonucleic acid (RNA) profile that may be exploited for the detection of pulmonary hypertension. Methods: Blood platelet RNA was isolated prospectively from 177 prevalent patients with different subtypes of pulmonary hypertension as well as 195 control subjects clinically not suspected of pulmonary hypertension. Sequencing libraries were created using SMARTer (Switching Mechanism at 59 end of RNA Template) copy desoxyribonucleic acid amplification and sequenced on the Illumina High Throughput Sequencing platform. RNA-sequencing reads were mapped to the human reference genome, and intron-spanning spliced RNA reads were selected. Differential spliced RNA panels were calculated by analysis of variance statistics. A particle swarm optimizationenhanced classification algorithm was built employing a development (n = 213 samples) and independent validation series (n = 159 samples). Results: We detected a total of 4,014 different RNAs in blood platelets from patients with pulmonary hypertension (n = 177) and asymptomatic control subjects (n = 195). Gene ontology analysis revealed enhanced RNA concentrations for genes related to RNA processing, translation, and mitochondrial function. A particle swarm optimizationselected RNA panel of 408 distinctive differentially spliced RNAs mediated detection of pulmonary hypertension with 93% sensitivity, 62% specificity, 77% accuracy, 0.89 (95% confidence interval, 0.83-0.93) area under the curve, and a negative predictive value of 91% in the independent validation series. The prediction score was independent of age, sex, smoking, pulmonary hypertension subtype, and the use of pulmonary hypertension-specific medication or anticoagulants. Conclusions: A platelet RNA panel may accurately discriminate patients with pulmonary hypertension from asymptomatic control subjects. In the light of current diagnostic delays, this study is the starting point for further development and evaluation of a platelet RNA-based blood test to ultimately improve early diagnosis and clinical outcomes in patients with pulmonary hypertension.

BackgroundThe clinical phenotype of idiopathic pulmonary arterial hypertension (IPAH) patients has changed. . Whether or not subgroups of IPAH patients have different vascular phenotypes is a subject of debate.Research questionWhat are the histological patterns and their clinical correlates in patients diagnosed with IPAH or hereditary PAH?Study design and MethodsIn this this cross-sectional registry study lung histology of 50 IPAH patients was qualitatively assessed by two experienced pathologists. In addition, quantitative analysis by means of histopathological morphometry using immunohistochemistry was performed. Histopathological characteristics were correlated with clinical and hemodynamic parameters.ResultsIn this cohort of 50 IPAH patients, a plexiform vasculopathy was observed in 26/50 (52%) of patients, while 24/50 (48%) patients had a non-plexiform vasculopathy. The non-plexiform vasculopathy was characterized by prominent pulmonary microvascular (arterioles and venules) remodeling and vascular rarefaction. While hemodynamic parameters were comparable in plexiform versus non-plexiform vasculopathy, patients with non-plexiform vasculopathy were older, more often male, had a stronger history of cigarette smoking and lower diffusing capacity for carbon monoxide (DLCO) at diagnosis No mutations in established PAH genes were found in the non-plexiform group.InterpretationThis study reveals different vascular phenotypes within the current spectrum of patients diagnosed with IPAH, separated by clinical characteristics (age, sex, , history of cigarette smoking, and DLCO at diagnosis). Potential differences in underlying pathobiological mechanisms between patients with plexiform and non-plexiform / microvascular disease should be taken into account in future research strategies unravelling the pathophysiology of pulmonary hypertension and developing biology-targeted treatment approaches.

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′O2) <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.

Fibrodysplasia Ossificans Progressiva (FOP) is a genetic disease characterized by the formation of heterotopic ossification (HO) in connective tissues. HO first develops in the thoracic region, before more peripheral sites are affected. Due to HO along the thoracic cage, its movements are restricted and pulmonary function deteriorates. Because development of HO is progressive, it is likely that pulmonary function deteriorates over time, but longitudinal data on pulmonary function in FOP are missing. Longitudinal pulmonary function tests (PFTs) from seven FOP patients were evaluated retrospectively to assess whether there were changes in pulmonary function during aging. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), total lung capacity (TLC), residual volume (RV) and diffusing lung capacity for carbon dioxide divided by alveolar volume (DLCO/VA) were included. In addition, HO volume along the thorax together with its progression as identified by whole body low dose CT scans were correlated to PFT data. Per patient, aged 7–57 years at the time of the first PFT, three to nine PFTs were available over a period of 6–18 years. Restrictive pulmonary function, identified by TLC or suspected by FVC, was found in all, but one, patients. In three patients, TLC, FVC or both decreased further during the follow-up period. All, but one, patients had an increased RV. The DLCO/VA ratio was normal in all FOP patients. Interestingly, FEV1 increased after a surgical intervention to unlock the jaw. In four out of five patients total HO volume in the thoracic region progressed beyond early adulthood, but no further decline in FVC was observed. In conclusion, restrictive pulmonary function was found in the majority of patients already at an early age. Our data suggest that the deterioration in pulmonary function is age dependent.

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.

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

AimHaemodynamic normalisation is the ultimate goal of pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). However, whether normalisation of haemodynamics translates into normalisation of exercise capacity is unknown. The incidence, determinants and clinical implications of exercise intolerance after PEA are unknown. We performed a prospective analysis to determine the incidence of exercise intolerance after PEA, assess the relationship between exercise capacity and (resting) haemodynamics and search for preoperative predictors of exercise intolerance after PEA.MethodsAccording to clinical protocol all patients underwent cardiopulmonary exercise testing (CPET), right heart catheterisation and cardiac magnetic resonance (CMR) imaging before and 6 months after PEA. Exercise intolerance was defined as a peak oxygen consumption (V′O2) <80% predicted. CPET parameters were judged to determine the cause of exercise limitation. Relationships were analysed between exercise intolerance and resting haemodynamics and CMR-derived right ventricular function. Potential preoperative predictors of exercise intolerance were analysed using logistic regression analysis.Results68 patients were included in the final analysis. 45 (66%) patients had exercise intolerance 6 months after PEA; in 20 patients this was primarily caused by a cardiovascular limitation. The incidence of residual pulmonary hypertension was significantly higher in patients with persistent exercise intolerance (p=0.001). However, 27 out of 45 patients with persistent exercise intolerance had no residual pulmonary hypertension. In the multivariate analysis, preoperative transfer factor of the lung for carbon monoxide (TLCO) was the only predictor of exercise intolerance after PEA.ConclusionsThe majority of CTEPH patients have exercise intolerance after PEA, often despite normalisation of resting haemodynamics. Not all exercise intolerance after PEA is explained by the presence of residual pulmonary hypertension, and lower preoperativeTLCOwas a strong predictor of exercise intolerance 6 months after PEA.

In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and may be hindered by competition and non-equivalent cooperation inherent in a hierarchical structure. Here we describe the "collaborative organizational model" of the Amsterdam Bone Center (ABC), which emerged from and benefited the rare bone disease team. This team is often confronted with pathologically complex and under-investigated diseases. We describe the benefits of this model that still guarantees the autonomy of each team member, but combines and focuses our collective expertise on a clear shared goal, enabling us to capture synergistic and innovative opportunities for the patient, while avoiding self-interest and possible harmful competition.

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.

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