Role of Forkhead box F1 in the Pathobiology of Pulmonary Arterial Hypertension.

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.

Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study.

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.

Deep phenotyping of unaffected carriers of pathogenic BMPR2 variants screened for pulmonary arterial hypertension.

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 Bmpr2Δ71Ex1/+ 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. Bmpr2Δ71Ex1/+ 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 Bmpr2Δ71Ex1/+ transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.

Optimisation of detecting chronic thromboembolic pulmonary hypertension in acute pulmonary embolism survivors: the InShape IV study.

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, N­terminal 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.

Clinical Correlates of a Nonplexiform Vasculopathy in Patients With a Diagnosis of Idiopathic Pulmonary Arterial Hypertension.

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.

The alveolar fibroproliferative response in moderate to severe COVID-19-related acute respiratory distress syndrome and 1-yr follow-up.

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.

Long-term effects of pulmonary endarterectomy on pulmonary hemodynamics, cardiac function, and exercise capacity in chronic thromboembolic pulmonary hypertension.

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.

Toward the Implementation of Optimal Cardiac Magnetic Resonance Risk Stratification in Pulmonary Arterial Hypertension.

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.

Long-Term Effects of Pulmonary Endarterectomy on Right Ventricular Stiffness and Fibrosis in Chronic Thromboembolic Pulmonary Hypertension.

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/m2 (-15.9 g/m2 [95% CI, -21.4 to -10.5]; P<0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m2 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 (Pinteraction=0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-ß (transforming growth factor-ß) 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.

Chronic thromboembolic pulmonary hypertension: realising the potential of multimodal management.

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.

Right Atrial Adaptation to Precapillary Pulmonary Hypertension: Pressure-Volume, Cardiomyocyte, and Histological Analysis.

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 mm2 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.

Restoration of right ventricular function in the treatment of pulmonary arterial hypertension.

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; pinteraction<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.

Automated quantification of the pulmonary vasculature in pulmonary embolism and chronic thromboembolic pulmonary hypertension.

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 (ß) 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.

Right Ventricular Function During Exercise After Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension.

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.

Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

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.

Positron Emission Tomography to Improve Assessment of Interstitial Lung Disease in Patients With Systemic Sclerosis Eligible for Autologous Stem Cell Transplantation.

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 18F-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.

Idiopathic pulmonary arterial hypertension patients with a high H2FPEF-score: Insights from the Amsterdam UMC PAH-cohort.

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 H2FPEF-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 H2FPEF-score; a score ≥5 identified a higher possibility of (concealed) LVDD. RESULTS: The presence of a high H2FPEF-score in incident iPAH-patients rose 30% in thirty years. Patients with a H2FPEF-score ≥5 were older, more often male and/or obese, and had more comorbidities than patients with a H2FPEF-score ≤1. A high H2FPEF-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 H2FPEF-score. At follow-up, hemodynamic and functional responses were similar in iPAH-patients with a high or low H2FPEF-score. CONCLUSIONS: While a high H2FPEF-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 H2FPEF-score.

Noninvasive follow-up strategy after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

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.

When right ventricular pressure meets volume: The impact of arrival time of reflected waves on right ventricle load in pulmonary arterial hypertension.

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.