RATIONALE: The European Respiratory and Cardiology Societies, as well as the World Symposium on Pulmonary Hypertension, recently adopted a definition of exercise pulmonary hypertension (ePHslope) as the slope of the mean pulmonary arterial pressure (mPAP) to cardiac output (CO) ratio during exercise as >3 mmHg min L-1, most likely due to its correlation with mortality. Another potential definition that was considered for peak values at peak exercise (ePHpeak) included mean pulmonary artery pressure (mPAPpeak) ≥30 mmHg with a peak total pulmonary resistance (TPRpeak) ≥3 WU. Both definitions essentially identify a TPR cutoff of 3 WU as abnormal, however, there remains inconsistent agreement between these different methodologies to identify ePH. Pulmonary vascular distensibility (alpha) is a sensitive indicator of early pulmonary vascular disease; it is a dynamic measurement of the percentage change in diameter per mmHg increase in the distending pressure of the pulmonary vasculature and is a valuable parameter of pulmonary vascular health. This study aims to investigate whether patients identified by ePHslope exhibit a lower alpha when compared to those with ePHpeak. METHODS: We performed cardiopulmonary and hemodynamic retrospective analysis in 63 patients who presented with exercise intolerance, evaluated using invasive cardiopulmonary exercise testing (iCPET).All patients had rest supine mPAP ≤25 mmHg and PAWP ≤15 mmHg. RESULTS: We identified 32 patients by ePHslope and 31 patients by ePHpeak. ePHslope subjects had lower median (IQR) alpha [0.71 (0.42 to 1.04)] compared to ePHpeak subjects [1.08 (0.71 to 1.25)] (p = 0.006). At peak exercise, alpha exhibited a positive correlation with pulmonary artery compliance (PAC) (r=0.26, p=0.038), lactate (r=0.27, p=0.029), oxygen consumption (VO₂) (r=0.31, p=0.014) and the slope of VO₂/workload (r=0.33, p=0.017). Alpha was inversely correlated with pulmonary vascular resistance (PVR) (r=-0.38, p=0.002), transpulmonary gradient (TPG) (r=-0.28, p=0.028) and the slope of mPAP/CO (r=-0.40, p=0.001). CONCLUSION: Patients identified by the ePHslope criteria showed significantly reduced pulmonary vascular distensibility (alpha) compared to those identified by ePHpeak, suggesting that the slope-based method more effectively captures early vascular stiffness and impaired compliance in exercise pulmonary hypertension. These findings support the ePHslope criteria as a more sensitive marker for identifying patients with compromised pulmonary vascular health, who may be at elevated risk for disease progression.

BACKGROUND:The direct Fick principle is the standard for calculating cardiac output (CO) to detect CO-dependent conditions like exercise pulmonary hypertension (ePH). Fick COarterial incorporates arterial haemoglobin (Hba) and oxygen saturation (S aO2 ) with oxygen consumption from exercise testing, while Fick COnon-arterial substitutes mixed venous haemoglobin (Hbmv) and peripheral oxygen saturation (S pO2 ) in the absence of an arterial line. The decision to employ an arterial catheter for exercise testing varies, and discrepancies in oxygen saturation and haemoglobin between arterial and non-arterial methods may lead to differences in Fick CO, potentially affecting ePH classification. METHODS:We performed a retrospective analysis of 296 consecutive invasive cardiopulmonary exercise testing (iCPET) studies comparing oxygen saturation from pulse oximetry (S pO2 ) and radial arterial (S aO2 ), Hba and Hbmv, and CO calculated with arterial (COarterial) and non-arterial (COnon-arterial) values. We assessed the risk of misclassification of pre- and post-capillary ePH and data loss due to inaccurate S pO2 . RESULTS:When considering all stages from rest to peak exercise, Hba and Hbmv demonstrated high correlation, while S pO2 and S aO2 as well as COarterial and COnon-arterial demonstrated low correlation. Data loss was significantly higher across all stages of exercise for S pO2 (n=346/1926 (18%)) compared to S aO2 (n=17/1923 (0.88%)). We found that pre- and post-capillary ePH were misclassified as COnon-arterial data (n=7/41 (17.1%) and n=2/23 (8.7%), respectively). Patients with scleroderma and/or Raynaud's (n=11/33 (33.3%)) and black patients (n=6/19 (31.6%)) had more S pO2 data loss. CONCLUSION:Reliance upon S pO2 during invasive exercise testing results in the misclassification of pre- and post-capillary ePH, and unmeasurable S pO2 for black, scleroderma and Raynaud's patients can preclude accurate exercise calculations, thus limiting the diagnostic and prognostic value of invasive exercise testing without an arterial line.

Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.

Objective To characterise subphenotypes of self-reported symptoms and outcomes (SRSOs) in postacute sequelae of COVID-19 (PASC).Design Prospective, observational cohort study of subjects with PASC.Setting Academic tertiary centre from five clinical referral sources.Participants Adults with COVID-19 ≥20 days before enrolment and presence of any new self-reported symptoms following COVID-19.Exposures We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardised assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via quantitative PCR.Outcomes measures Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA) and relationship with viral load.Results We analysed baseline data for 214 individuals with a study visit at a median of 197.5 days after COVID-19 diagnosis. Participants reported ever having a median of 9/16 symptoms (IQR 6–11) after acute COVID-19, with muscle-aches, dyspnoea and headache being the most common. Fatigue, cognitive impairment and dyspnoea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3 (1–6)) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%) and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001) as well as referral source for enrolment. Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes.Conclusions We identified three distinct PASC subphenotypes. We highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.

BACKGROUND:Preload insufficiency is an underrecognized cause of exercise intolerance identified during invasive cardiopulmonary exercise testing, and defined hemodynamically by decreased biatrial filling pressures, cardiac output, and oxygen consumption (V̇O2) at peak effort. Patients with preload insufficiency, however, typically present with symptoms of dyspnea on exertion, and/or exercise intolerance at submaximal efforts, particularly when performing activities of daily living. The cardiopulmonary hemodynamics and physiology at submaximal work levels of preload insufficiency have not been previously investigated. We hypothesized that preload insufficiency hemodynamics exist along a continuum, with submaximal exercise values reflecting peak exercise cardiopulmonary hemodynamics. METHODS:We compared submaximal cardiopulmonary hemodynamics, measured at anaerobic threshold, between preload insufficiency patients and age-matched controls referred for dyspnea but with normal exercise responses. RESULTS:Our study included 66 patients: 41 with preload insufficiency and 25 controls. Preload insufficiency patients exhibit significantly reduced V̇O2, watts, and METS at submaximal levels compared to controls, alongside earlier anaerobic threshold achievement and similar heart rates at anaerobic threshold. CONCLUSIONS:These findings underscore the profound impact of preload insufficiency on submaximal exercise capacity, emphasizing the importance of its recognition and management. This insight sets the stage for further investigations into interventions targeting preload insufficiency at submaximal exercise levels to enhance both exercise performance and quality of life.

Background Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study ( ClinicalTrials.gov : NCT03496623 ) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. Methods Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. Results In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. Conclusions The risk–benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.

Invasive cardiopulmonary exercise testing (iCPET) is increasingly recognized as a critical diagnostic tool for assessing exercise intolerance and dyspnea. The manuscript highlights the iCPET program's diagnostic precision in identifying various cardiopulmonary disorders, offering insights into tailored treatment strategies. This guide aims to assist institutions in establishing their iCPET programs, addressing both the technical and administrative facets essential for success. The narrative is rooted in personal experiences, reflecting on the demanding, yet rewarding, journey of enhancing patient care through advanced diagnostic capabilities.

Objectives: To evaluate the prognostic utility of CT-imaging-derived biomarkers in distinguishing acute pulmonary embolism (PE) resolution and its progression to chronic PE, as well as their association with clot burden. Materials and Methods: We utilized a cohort of 45 patients (19 male (42.2%)) and 96 corresponding CT scans with exertional dyspnea following an acute PE. These patients were referred for invasive cardiopulmonary exercise testing (CPET) at the University of Pittsburgh Medical Center from 2018 to 2022, for whom we have ground truth classification of chronic PE, as well as CT-derived features related to body composition, cardiopulmonary vasculature, and PE clot burden using artificial intelligence (AI) algorithms. We applied Lasso regularization to select parameters, followed by (1) Ordinary Least Squares (OLS) regressions to analyze the relationship between clot burden and the selected parameters and (2) logistic regressions to differentiate between chronic and resolved patients. Results: Several body composition and cardiopulmonary factors showed statistically significant association with clot burden. A multivariate model based on cardiopulmonary features demonstrated superior performance in predicting PE resolution (AUC: 0.83, 95% CI: 0.71–0.95), indicating significant associations between airway ratio (negative correlation), aorta diameter, and heart volume (positive correlation) with PE resolution. Other multivariate models integrating demographic features showed comparable performance, while models solely based on body composition and baseline clot burden demonstrated inferior performance. Conclusions: Our analysis suggests that cardiopulmonary and demographic features hold prognostic value for predicting PE resolution, whereas body composition and baseline clot burden do not. Clinical Relevance: Our identified prognostic factors may facilitate the follow-up procedures for patients diagnosed with acute PE.

We present a novel computer algorithm to automatically detect and segment pulmonary embolisms (PEs) on computed tomography pulmonary angiography (CTPA). This algorithm is based on deep learning but does not require manual outlines of the PE regions. Given a CTPA scan, both intra- and extra-pulmonary arteries were firstly segmented. The arteries were then partitioned into several parts based on size (radius). Adaptive thresholding and constrained morphological operations were used to identify suspicious PE regions within each part. The confidence of a suspicious region to be PE was scored based on its contrast in the arteries. This approach was applied to the publicly available RSNA Pulmonary Embolism CT Dataset (RSNA-PE) to identify three-dimensional (3-D) PE negative and positive image patches, which were used to train a 3-D Recurrent Residual U-Net (R2-Unet) to automatically segment PE. The feasibility of this computer algorithm was validated on an independent test set consisting of 91 CTPA scans acquired from a different medical institute, where the PE regions were manually located and outlined by a thoracic radiologist (>18 years' experience). An R2-Unet model was also trained and validated on the manual outlines using a 5-fold cross-validation method. The CNN model trained on the high-confident PE regions showed a Dice coefficient of 0.676±0.168 and a false positive rate of 1.86 per CT scan, while the CNN model trained on the manual outlines demonstrated a Dice coefficient of 0.647±0.192 and a false positive rate of 4.20 per CT scan. The former model performed significantly better than the latter model (p<0.01). The promising performance of the developed PE detection and segmentation algorithm suggests the feasibility of training a deep learning network without dedicating significant efforts to manual annotations of the PE regions on CTPA scans.