Exercise testing has long been essential for evaluating diagnosis, prognosis, and functional status in pulmonary hypertension (PH). Recent advances have clarified its role in defining reference values and prognostic markers. Nonetheless, substantial knowledge gaps persist regarding the implementation of invasive cardiopulmonary exercise testing (iCPET) and its potential to inform pathophysiology and therapeutic decision-making. This statement addresses the knowledge gaps that hinder the application of iCPET and exercise right heart catheterization (RHC) in the assessment of PH. We present research priorities and scenarios in which these tests may clarify drug mechanisms and support PH subphenotyping. An international, multidisciplinary task force of cardiology and pulmonology experts reviewed the literature and formulated consensus recommendations through iterative discussions.

A deterioration in K CO or T LCO by ∼5% pred per year or any rise in BNP in patients with fibrotic ILD should prompt echocardiography and thereafter referral for invasive assessment by RHC in a PH centre, as appropriate https://bit.ly/4ozSdbb.

Abstract Background/Aims Pulmonary arterial hypertension (PAH) is a rare but severe complication of connective tissue disease (CTD), including systemic lupus erythematosus (SLE). Immune-mediated pulmonary vascular remodelling and endothelial dysfunction drive rapid haemodynamic deterioration and high mortality. Current guidelines recommend parenteral prostacyclin therapy, such as intravenous epoprostenol, for high-risk PAH (WHO Functional Class IV). In contrast to idiopathic disease, PAH associated with inflammatory CTD, such as SLE, may demonstrate reversibility with timely immunosuppression. Methods A 35-year-old lady with active SLE on long-term hydroxychloroquine, diagnosed in 2017 on the basis of positive anti-dsDNA antibodies, low complement C3/C4, positive antiphospholipid antibodies, autoimmune haemolytic anaemia, and thrombocytopenia, presented with progressive exertional dyspnoea, presyncope, and peripheral oedema. Echocardiography demonstrated right ventricular dilatation and dysfunction, elevated pulmonary artery pressures and pericardial effusion. Before urgent transfer to the national pulmonary hypertension centre for further evaluation, she was commenced on prednisolone 1mg/kg for active lupus and autoimmune thrombocytopenia. Right heart catheterisation (RHC) confirmed pre-capillary pulmonary hypertension with mean pulmonary artery pressure (mPAP) of 66mmHg, consistent with severe pulmonary hypertension, while CT lungs and ventilation-perfusion scanning excluded alternative causes. According to ESC/ERS 2022 guidelines, she was classified as high risk, warranting upfront triple combination therapy including intravenous epoprostenol. However, severe thrombocytopenia (platelets 19 × 109/L, normal: 150-400) made prostacyclin therapy unsafe due to bleeding risk. A multidisciplinary team involving rheumatology, haematology, and pulmonary hypertension specialists determined that bleeding risk outweighed potential haemodynamic benefit at the time. Intensive immunosuppression with corticosteroids and rituximab was therefore commenced, aiming to improve thrombocytopenia. Oral dual pulmonary vasodilator therapy with a phosphodiesterase-5 inhibitor (tadalafil) and an endothelin receptor antagonist (macitentan) was initiated cautiously, resulting in clinical stabilisation. Results Over two weeks, NT-proBNP levels, symptoms, and exercise tolerance improved. Platelets improved to 124 × 109/L. Repeat echocardiography showed marked improvement in right ventricular size and function with reduced systolic pressures; RHC showed mPAP of 37mmHg (moderate PAH). Her risk status improved from high to intermediate risk, and a third oral vasodilator, selexipag, was subsequently introduced. Conclusion PAH is a recognised but uncommon and life-threatening manifestation of SLE. Unlike idiopathic PAH, the pathophysiology in SLE often involves immune-mediated endothelial injury and pulmonary vascular remodelling, creating a therapeutic window where early immunosuppression can improve outcomes. Current ESC/ERS guidelines recommend parenteral prostacyclin therapy for high-risk disease; however, treatment must be individualised when complications like thrombocytopenia increase bleeding risk. In this case, profound thrombocytopenia precluded standard high-intensity vasodilator therapy. A multidisciplinary approach enabled tailored management with prompt immunosuppression (corticosteroids and rituximab) alongside oral dual vasodilator therapy, leading to significant clinical and echocardiographic improvement. This highlights the importance of potential reversibility of SLE-associated PAH with timely immunosuppression and importance of multidisciplinary, individualised care in complex presentations where standard therapy poses risk. Disclosure W. Lai: None. L. Price: None. C. McCabe: None. S.J. Wort: None. M. Fernando: None. H. Nashat: None.

Abstract Background The 2022 ESC/ERS guidelines redefined pulmonary hypertension (PH) as a mean pulmonary artery pressure (mPAP) >20 mmHg on right heart catheterisation (RHC). Echocardiography, using metrics such as tricuspid regurgitation velocity (TRV), tricuspid annular plane systolic excursion (TAPSE), and TAPSE/systolic pulmonary artery pressure (TAPSE/SPAP), guides referral for RHC. However, the few studies evaluating echocardiographic performance using the ESC/ERS 2022 thresholds have combined the newly included population as a relatively modest subgroup within their overall analysis. Results We present a sample of 1,991 individuals from the EVIDENCE-PAH UK database. Our data demonstrate higher TRV and sPAP values and lower TAPSE/SPAP values with higher haemodynamic category. ROC analysis demonstrates that TRV, SPAP and TAPSE/SPAP perform well as predictors of mPAP > 20 mmHg and ≥25 mmHg (AUCs 0.785–0.830), but less well at predictive mPAP 21–24 mmHg (AUCs 0.656–0.686). In all PH patients and the mild PH (21–24 mmHg) subgroup, TAPSE/SPAP < 0.31 mm/mmHg predicted reduced survival (HR 2.01–3.14, p < 0.001). Similarly, in haemodynamically mild PH, TRV > 3.4 m/s was associated with worse survival compared to TRV < 2.5 m/s or 2.5–2.8 m/s (p < 0.001). Conclusions While established echocardiographic metrics (TRV, TAPSE/SPAP) are strong predictors of significant PH (mPAP ≥25 mmHg), they are less accurate for mild PH (mPAP 21–24 mmHg). Importantly, mild PH itself is associated with increased mortality, and within this group, TRV >3.4 m/s and TAPSE/SPAP <0.31 mm/mmHg identify patients at highest risk, supporting their prognostic utility even in early haemodynamic disease.

Preclinical studies suggest beneficial effects of GLP-1 agonists in pulmonary arterial hypertension (PAH). This first-in-disease study evaluated acute hemodynamic effects of GLP-1 agonist, exenatide administered i.v. in patients with idiopathic PAH and CTEPH as well as in a PAH rodent model. Seventeen patients (9 idiopathic PAH) received an exenatide infusion during right heart catheterization, which included multisite sampling for circulating metabolites. Acute effects of exenatide were also assessed by cardiac magnetic resonance imaging in monocrotaline (MCT) PAH and control rats. In the clinical study, exenatide was well tolerated, reduced mean pulmonary artery pressure (45 ± 15 mmHg versus 40 ± 18 mmHg), and improved cardiac index (2.1 ± 0.6 L/min versus 2.4 ± 0.9 L/min/m 2 ) and pulmonary vascular resistance (7.8 ± 8.0 WU versus 5.9 ± 5.0 WU) across all patients. Right ventricular (RV) contractility and afterload improved in a subset of patients undergoing pressure-volume measurements. In an exploratory metabolomics analysis, 47 metabolite levels changed after exenatide infusion, predominantly in free fatty acid pathways. Six metabolites with prognostic relevance in PAH within myocardial glycolytic and lipid oxidation pathways were also altered after exenatide. In MCT rats, exenatide improved RV stroke-volume, RV ejection fraction, and RV-arterial coupling. These findings support the further evaluation of exenatide within chronic studies as a potentially novel pulmonary vasodilator therapy.

Aims:Vasorelaxant and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) agonists support their investigation in aiding the recovery of patients with acute pulmonary embolism (PE) at risk of worse outcomes. Methods:We undertook a four week non-randomized, controlled open-label study examining proteomic changes, markers of vascular inflammation and exploratory imaging endpoints in response to GLP-1 agonist, semaglutide (0.25 mg weekly) added to standard of care anticoagulation in patients with intermediate high-risk PE. Results:44 plasma proteins were downregulated in response to semaglutide that were significantly enriched for glycoproteins (false discovery rate q < 0.01). Glycopeptide analysis of highly abundant glycoproteins between diagnosis and follow-up demonstrated a reduction in glycopeptide abundance suggesting protein deglycosylation as a possible mechanism of glycoprotein down-regulation. Down-regulated proteins included regulators of metabolic stress and complement pathway intermediates, which were at higher abundance in PE patients at diagnosis compared to age and sex-matched controls without PE (all P < 0.001). Exploratory evaluation of radiological markers of right ventricular dysfunction improved from baseline to follow-up only in patients who received semaglutide (P < 0.01). Conclusions:These findings suggest merit in wider investigation of immunometabolic changes in the plasma proteome during acute PE recovery and their potential relevance to modulation using GLP-1 agonists. Registration:The study was registered under clinicaltrials.org (NCT06118203).

This is the first study to compare well-phenotyped patients with ILD-PH in a single centre. Unlike broader cohorts, once PH is severe enough to warrant RHC, survival appears independent of the underlying ILD subtype when comparing IPF-PH with non-IPF-PH. https://bit.ly/3IimPxW.

Interstitial lung disease (ILD) registries suggest that survival is dependent upon ILD subtype. However, once pulmonary hypertension (PH) intervenes, survival is considered to be driven by PH irrespective of the underlying ILD subtype. To date, this has been based on studies of individual conditions rather than direct comparison of PH-ILD subtypes. Therefore, we studied the survival of patients with non-connective tissue disease ILD and right heart catheterisation (RHC)-confirmed PH managed at a tertiary centre. Patients with PH associated with IPF, chronic hypersensitivity pneumonitis (CHP), idiopathic NSIP, post-COVID-19 ILD, or unclassifiable ILD referred between 2006 and 2023 were identified. Baseline data comprising demographic, haemodynamic (RHC), pulmonary function, six-minute walk distance (6MWD), emPHasis-10 score (since 2014), WHO functional class, brain natriuretic peptide (BNP), and echocardiographic measurements were collected within one year before or two months after PH diagnosis. 131 patients were identified: PH-IPF (n=83, 63.4%), PH-CHP (n=26, 19.8%), PH-NSIP (n=12, 9.2%), post-COVID-19 PH-ILD (n=6, 4.6%) and PH-unclassifiable ILD (n=4, 3.1%). Most (62.6%) were male, with a median age of 67.5 (60.5-73.9) years at diagnosis, and a median follow-up of 1.1 (0.6-2.1) years. Over half of the cohort (n=76, 58.0%) had severe PH defined by a PVR>5WU. 1-, 3-, and 5-year survival was 53.2%, 18.8% and 6.3%, respectively, with a median time to death or lung transplant of 1.2 (0.5-2.2) years. Survival by subtype (IPF vs non-IPF) demonstrated no survival difference (log-rank p=0.11), with 1-, 3-, and 5-year survival as follows: PH-IPF (49.3%, 17.4%, 4.4%); PH-CHP (53.1%, 13.4%, 13.4%), PH-NSIP (75%, 42.9%, 10.7%), post-COVID PH-ILD (83.3% at 1 year), and unclassifiable PH-ILD (25%, 0%, 0%). Univariate analysis identified six parameters associated with a death/transplant: male gender (HR 1.49[1.00-2.20], p=0.049); FVC% (HR 0.99[0.98-1.00], p=0.04); TLco% (HR 0.95[0.93-0.98], p<0.001); 6MWD <225m (HR 2.35[1.45-3.82], p<0.001); BNP>100ng/L (HR 1.63[1.09-2.45], p=0.018); and RV dysfunction (HR 1.84[1.22-2.77] p<0.01). Stepwise backward multivariate analysis revealed TLco% and BNP>100ng/L as predictors of death or transplant. This report is the first single-centre study to compare outcomes between subtypes of PH-ILD and demonstrates that, following onset of PH, survival is independent of ILD subtype. Furthermore, we demonstrate on multivariate analysis that mortality is associated with gas transfer impairment and BNP, the latter highlighting the importance of RV dysfunction in this high-risk patient group and advocating monitoring with serial measures to inform prognosis and treatment stratification.

Background: Glucagon-like peptide-1 (GLP-1) agonists are an existing treatment option for patients with insulin-resistant states, which elicit further pleiotropic effects related to immune cell recruitment and vascular inflammation. GLP-1 agonists downregulate the cluster of differentiation 147 (CD147) receptor, one of several receptors for the SARS-CoV-2 spike protein that mediate viral infection of host cells. Methods: We conducted an open-label prospective safety and tolerability study including biomarker responses of the GLP-1 agonist Liraglutide, administered for 5 days as an add-on therapy to the standard of care within 48 h of presentation in a cohort of 13 patients hospitalized with COVID-19 pneumonia. Biomarker responses were compared in patients admitted to critical care and those not requiring critical care admission (non-critical group). Results: Liraglutide (0.6 mg, subcutaneously) was well tolerated by all patients and all patients were alive 30 days after diagnosis. Plasma soluble CD147 levels were reduced in the non-critical patient group at day 5 in contrast to critical care-treated patients, who demonstrated an increase in soluble CD147 levels between day 0 and day 5. Patients with milder COVID-19 pneumonia severity also demonstrated improvement in echocardiographic parameters of right and left ventricular function, reduction in plasma Troponin levels, increased CD147 expression on T lymphocytes, and reduction in plasma IL-8. Conclusions: This first-in-disease use of the GLP-1 agonist Liraglutide demonstrates its safety and tolerability in an unselected cohort of patients hospitalized with COVID-19 pneumonia across a range of clinical severities.

Dietary nitrate supplementation, which improves skeletal muscle oxygen utilisation, vascular endothelial function and exercise capacity in people with chronic obstructive pulmonary disease, may benefit other lung conditions. In a double-blind, placebo-controlled, crossover study, in 19 adults with Group 3 pulmonary hypertension who desaturated during exercise, 140 mL of nitrate-rich beetroot juice improved endurance shuttle walk time compared with nitrate-depleted beetroot juice placebo (median (IQR) ESWT NR-BRJ 197 (140–273) s vs PL-BRJ 174 (107–229) s; median difference (MD) (95% CI) 30 (6.19 to 91.07) s, p=0.0281), endothelial function, flow-mediated dilatation (+3.40±5.47% vs −1.33±4.78; MD (95% CI) 4.73 (1.44 to 8.02), p=0.007) and lowered mean arterial blood pressure (−3.9 (−7.4 to −0.4) mm Hg, p=0.028).

Pulmonary hypertension (PH) is highly prevalent in patients with interstitial lung disease (ILD) and is associated with increased morbidity and mortality. Widely available noninvasive screening tools are warranted to identify patients at risk for PH, especially severe PH, that could be managed at expert centres. This review summarises current evidence on noninvasive diagnostic modalities and prediction models for the timely detection of PH in patients with ILD. It critically evaluates these approaches and discusses future perspectives in the field. A comprehensive literature search was carried out in PubMed and Scopus, identifying 39 articles that fulfilled inclusion criteria. There is currently no single noninvasive test capable of accurately detecting and diagnosing PH in ILD patients. Estimated right ventricular pressure (RVSP) on Doppler echocardiography remains the single most predictive factor of PH, with other indirect echocardiographic markers increasing its diagnostic accuracy. However, RVSP can be difficult to estimate in patients due to suboptimal views from extensive lung disease. The majority of existing composite scores, including variables obtained from chest computed tomography, pulmonary function tests and cardiopulmonary exercise tests, were derived from retrospective studies, whilst lacking validation in external cohorts. Only two available scores, one based on a stepwise echocardiographic approach and the other on functional parameters, predicted the presence of PH with sufficient accuracy and used a validation cohort. Although several methodological limitations prohibit their generalisability, their use may help physicians to detect PH earlier. Further research on the potential of artificial intelligence may guide a more tailored approach, for timely PH diagnosis.