Abstract Background Iron deficiency (ID) is common in patients with pulmonary arterial hypertension (PAH) and is associated with worse clinical outcomes. The etiology of ID in PAH is poorly understood. The aim of this study was to systematically determine whether differences in oral iron absorption exist between PAH patients with and without chronic ID compared with healthy controls. Methods This single-center prospective, cross-sectional cohort study enrolled 45 subjects: 15 PAH patients with chronic ID, 15 PAH patients without ID and 15 healthy age and sex matched controls. Chronic ID was defined by either recorded ID anemia or clinical indication for i.v. iron supplementation in the past 3 years. Plasma iron levels and transferrin saturation (TSAT) were measured before and after a standardized oral iron absorption test with 200 mg ferrous iron. Additional iron and inflammation laboratory parameters were determined. Hepcidin and erythroferrone levels were measured using enzyme-linked immunosorbent assay, and tumor necrosis factor alpha and ferroportin expression were determined by quantitative polymerase chain reaction. Results Both PAH groups showed a similar increase of plasma iron and TSAT after 3 h. The increase in plasma iron and TSAT was significantly lower in both PAH groups (with chronic ID: 71.5 (IQR 44.1–188.8) µg/dl; 22 (IQR 14–49) %; without ID: 86.0 (IQR 27.9–105.6) µg/dl; 26 (IQR 11–42) %) compared to healthy controls (154.1 (IQR 129.0–181.5) µg/dl; 45 (IQR 34–54) %, p = 0.015 and p = 0.031, respectively). Conclusions This study is the first to demonstrate a significantly reduced gastrointestinal iron uptake in PAH patients compared to healthy age and sex matched controls. Interestingly, PAH patients with chronic ID showed similar iron uptake levels as those without, suggesting that factors other than iron stores, such as chronic inflammation, may impair iron absorption in this patient population.

Background In heritable pulmonary arterial hypertension (HPAH) patients, bone morphogenetic protein receptor 2 (BMPR2) signalling and blood mRNA expression are disturbed and reduced. It is unclear whether BMPR2 expression is also altered in other PAH forms or in chronic thromboembolic pulmonary hypertension (CTEPH). Objective We aimed to investigate the expression of BMPR2 signalling pathway components in different subgroups of pulmonary hypertension (PH) patients and healthy controls. Methods In this multicentre, cross-sectional study, a total of 234 subjects were included in seven cohorts: 30 HPAH patients, 38 idiopathic PAH without and 40 idiopathic PAH with comorbidities, 38 systemic sclerosis associated PAH, 47 CTEPH patients, 9 healthy BMPR2 pathogenic variant carriers and 32 healthy controls. ELISAs and qPCR were performed on peripheral blood samples for BMP10, BMPR2, SMAD5, ID1, EIF2AK4. Univariate ANOVA was used to compare expression across groups. Results BMPR2 mRNA expression was significantly reduced in all PH subgroups compared to healthy controls (p<0.001). Lower BMPR2 mRNA expression correlated with worse hemodynamics. BMP10 protein expression showed significant differences between the analysed groups (p<0.001). Higher BMP10 protein levels correlated with worse cardiac output (p=0.005), WHO functional class (p=0.002), N-terminal pro-brain natriuretic peptide (p=0.003) and 6-minute walking distance (p=0.003). Conclusion Our data suggest that BMPR2 mRNA expression is not only significantly reduced in carriers of pathogenic BMPR2 variants, but also across all other assessed PAH subgroups and in CTEPH, indicating a potential general impairment of BMPR2 signalling. BMPR2 mRNA and BMP10 protein expression in blood may serve as novel biomarkers for disease severity.

BACKGROUND:Pulmonary arterial hypertension therapies have not been systematically studied in early disease stages, despite potential benefit. RESEARCH QUESTION:Is riociguat safe, well tolerated, and potentially effective in early pulmonary vascular disease? STUDY DESIGN AND METHODS:This was a prospective, multicenter, double-blind phase 2a trial. Adults with early pulmonary vascular disease, defined as mean pulmonary arterial pressure ≥ 25 mm Hg with pulmonary vascular resistance (PVR) ≥ 2 to < 3 Wood units (WU), or mean pulmonary arterial pressure 21 to < 25 mm Hg with PVR ≥ 2 WU, were randomized to receive 1:1 riociguat or placebo for 24 weeks. The primary end point was change in PVR from baseline to week 24. Secondary end points, evaluated hierarchically, comprised changes in cardiac index, total pulmonary resistance, diffusing capacity of the lung for carbon monoxide, 6-minute walking distance, World Health Organization functional class, and quality of life. Complementary parameters were analyzed in an exploratory manner, and safety was monitored throughout. RESULTS:Of 261 prescreened patients, 35 eligible patients were randomized to treatment (97% female; mean age, 65.5 ± 6.9 years; 77.1% connective tissue disease-associated pulmonary arterial hypertension); 32 completed the trial. Reasons for ineligibility were documented. Riociguat significantly improved the primary end point of change in PVR (riociguat -0.73 ± 0.67 WU vs placebo -0.02 ± 0.67 WU; P = .043; 27% placebo-adjusted reduction). No significant differences were observed in secondary end points. Of the exploratory end points, only cardiac output showed a trend toward improvement under riociguat (0.35 ± 0.86 L/min vs placebo -0.19 ± 0.75 L/min; P = .084). Only mild to moderate adverse events were observed, and serious events were not considered treatment related. INTERPRETATION:Despite the limited number of participants, treatment with riociguat was safe and significantly improved the primary end point PVR over 24 weeks. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT05339087; URL: www. CLINICALTRIALS:gov).

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by right ventricular (RV) pressure overload, dilatation and dysfunction, which are key prognostic determinants. While riociguat improves exercise capacity and hemodynamics, prospective data on reverse remodeling remain limited. This prospective, phase IV study evaluated the effects of riociguat on right-heart size, function, hemodynamics, exercise capacity and safety in PAH patients. Methods Treatment-naïve or pretreated PAH patients were enrolled. Patients receiving phosphodiesterase-5 inhibitors (PDE5i) could be switched to riociguat upon clinical indication. The primary endpoint was the change in right atrial (RA) and RV area at 24 weeks. Secondary endpoints included additional echocardiographic, clinical, exercise, hemodynamic and laboratory parameters, as well as quality-of-life (QoL) and safety. Results Thirty patients (61.2 ± 14.5 years; 76.7% male; 24 PDE5i-pretreated) were enrolled. Marked right-heart dilatation and impaired RV function were prominent at baseline. At week 24, riociguat significantly reduced RA (Δ -3.17 ± 5.91 cm²; p = 0.006) and RV area (Δ -6.00 ± 3.80 cm²; p < 0.0001). Furthermore, RV-fractional area change, 6-minute walking distance and functional class improved significantly. In patients with invasive follow-up, cardiac index increased significantly, with favorable trends in further parameters. N-terminal pro-brain natriuretic peptide and QoL remained unchanged. The study terminated early following the decision by the supplier Merck/MSD; the termination was not safety related. Riociguat was generally well tolerated with no new safety concerns. Conclusion Riociguat therapy resulted in a statistically significant improvement in right ventricular and atrial size and function with further improvements in exercise capacity and functional class. This prospective trial confirms the findings of previous retrospective studies and supports riociguat as an effective treatment option to improve RV geometry and performance. Trial registration This trial was registered on clinicaltrials.gov with the ClinicalTrials.gov ID NCT04954742.

INTRODUCTION:The clinical phenotype of pulmonary arterial hypertension (PAH) has shifted increasingly towards older patients with more cardiovascular comorbidities. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are used to treat symptomatic chronic heart failure. This study aimed to evaluate the impact of add-on SGLT2i in PAH patients with heart failure with preserved ejection fraction (HFpEF) as comorbidity. METHODS:PAH patients on stable therapy receiving SGLT2i as add-on were included in this single-center, retrospective cohort study. The primary endpoint comprised the change in echocardiographic right atrial (RA) area and right ventricular (RV) function after treatment with SGLT2i. Further clinical and echocardiographic parameters were analyzed. RESULTS:In total 198 patients on stable PAH therapy for at least three months receiving SGLT2i treatment and available follow-up assessments were analyzed (74±28 years, 61% female; 83.9% WHO functional class III-IV). During SGLT2i treatment, a significant reduction in RA area -1.93 ± 4.45 cm² (p<0.001) and improvement in RV function (p<0.001) during the mean follow-up of 6.7±3.3 months could be detected. RV area (-1.69±4.83 cm²), left atrial diameter (-2.17±4.43 mm) and systolic pulmonary arterial pressure (-9.26±16.10 mmHg) decreased significantly (all p<0.001). The mean 6-minute walking distance increased by 51.68±58.5 meters (p<0.001) and risk stratification significantly improved. Five patients discontinued the medication due to side effects. CONCLUSION:In patients with PAH and HFpEF as comorbidity SGLT2i as add-on to targeted therapy significantly improved right heart size and function, as well as further clinical parameters and was well tolerated. Further prospective studies are necessary to confirm these results.

INTRODUCTION:The objective of this study was to analyse the influence of fluid restriction (FR) on right heart size and clinical parameters in pulmonary arterial hypertension (PAH) patients with right heart failure (RHF). METHODS:In this prospective, single-centre, randomised, controlled study (Trial Registration: DRKS00029667), PAH patients with RHF and signs of volume overload were included. Intensified instructions for restriction of fluid intake to ≈1.5 l/d were compared to routine recommendation of FR. The primary endpoint was the change in right atrial (RA) and right ventricular (RV) area at follow-up. Secondary endpoints included haemodynamics, quality of life, symptoms and physical capacity. RESULTS:Overall, 41 PAH patients were included (70.2±12.0 years; 51.2% male; 70.7% WHO functional class III). During follow-up (mean 28.0±6.4 weeks) both groups showed comparable fluid intake reduction (intervention -0.56±0.51 l/d; control -0.57±0.71 l/d; all -0.57±0.60 l/d; p<0.001) with a significant improvement of the primary endpoint RA area (mean reduction -2.09±5.88 cm²; p=0.049) but not RV area (-1.12±4.48 cm²; p=0.160). Among secondary endpoints systolic pulmonary arterial pressure (sPAP, -7.90±14.68 mmHg; p=0.005), left ventricular eccentricity index (LV-EI, -0.09±0.22; p=0.020), mental health (6.67±18.57; p=0.047), physical function (8.03±20.04; p=0.028) and symptom burden (PAH-SYMPACT -4.33±10.23; p=0.021) improved significantly. CONCLUSION:The results of this controlled, prospective study demonstrate that FR to ≈1.5 l/d can significantly improve RA size and important clinical parameters in PAH patients as sPAP, LV-EI and quality of life. Notably, routine clinical counselling alone was sufficient to achieve effective fluid restriction, with no additional benefit observed from an intensified educational intervention.

Background: In healthy subjects, sex differences in right heart function have been detected for various echo- cardiographic parameters. The objective of this study was to investigate sex differences in echocardiographic European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk stratification parameters and their impact on survival estimation in patients with pulmonary arterial hypertension (PAH). Methods: In this retrospective, cross-sectional study with a mean follow-up time of 3.2 +/- 2.65 years (median, 2.78 years), clinical parameters including right atrial (RA) area, right ventricular area, and tricuspid annular plane systolic excursion (TAPSE) divided by systolic pulmonary artery pressure (sPAP) were assessed. Thresholds of ESC/ERS risk stratification were compared using multivariable Cox regression analysis. Results: Of 748 patients with PAH (mean age, 65 +/- 15 years; 63% women), men had significantly larger right heart size than women (RA area 21.76 +/- 7.64 vs 17.65 +/- 6.82 cm2, P < .001; right ventricular area 24.02 +/- 7.15 cm(2) vs 18.41 +/- 5.75 cm2, P < .001). This difference was consistent throughout all World Health Organization functional classes and cardiac index risk groups, except for the RA area in the cardiac index high-risk group and World Health Organization functional class IV. On multivariable analysis, indexed values showed more pronounced differences for age-adjusted survival analysis compared with ESC/ERS risk stratification thresholds. TAPSE/sPAP showed no significant sex differences, which makes this parameter a robust prognostic predictor. Conclusions: This is the first study focusing on sex differences in right heart size obtained by echocardiography in patients with PAH. For risk stratification indexing RA area to body surface area could be more reflective of body composition. In contrast, TAPSE/sPAP values were not sex dependent and were a robust prognostic factor in patients with PAH. (J Am Soc Echocardiogr 2025;38:273-85.)

This special issue summarizes, comments, and discusses the topics developed by the task forces at the 7th World Symposium on Pulmonary Hypertension in Barcelona in 2024 in consideration of recent literature. Particular attention is paid to the conditions in German-speaking countries. In addition to adjustments to the definition of the disease, diagnostics, and treatment of pulmonary hypertension, the pathophysiology of the right ventricle, genetic diagnostics, and imaging techniques are highlighted. Pulmonary hypertension in left heart disease, in lung disease, chronic thromboembolic pulmonary hypertension, pulmonary hypertension in children, and in adults with congenital heart disease are each presented and discussed in a separate article in the context of the guidelines and the World Congress.This special issue therefore provides a comprehensive overview of current topics and developments in the field of pulmonary hypertension.

INTRODUCTION:In pulmonary arterial hypertension (PAH), right heart (RH) failure is associated with high mortality and poor prognosis. The objective of this cohort study was to assess, whether reduction of fluid intake is associated with RH size and clinical outcome in PAH patients. METHODS:A retrospective, exploratory analysis of patients with invasively diagnosed PAH and signs of fluid retention who were routinely clinically monitored for 8.4 ± 5.3 months including fluid uptake and signs of RH failure was performed. Patients were advised to reduce fluid uptake to a maximum of 2 L per day (L/day) according to clinical routine. Clinical characteristics of patients with normal fluid intake <2 L/day vs. high fluid intake ≥2 L/day and patients who reduced vs. patients with increased fluid intake during follow-up were compared. Furthermore, the influence of hospitalization due to fluid overload and for treatment with intravenous diuretics at baseline and fluid intake on survival and time to clinical worsening (TTCW) were investigated. RESULTS:Out of 66 patients with signs of fluid retention at baseline (normal fluid intake <2 L/day, n = 16; high fluid intake ≥2 L/day, n = 50), 21 presented with hospitalization due to fluid overload, which was significantly associated with worse survival (p = 0.004) and TTCW (p < 0.001). During follow-up patients who reduced fluid intake <2 L/day presented with in trend reduced right ventricular area (p = 0.051) and longer TTCW (p = 0.007). Hospitalization due to fluid overload and fluid intake during follow-up were independent predictors of TTCW. CONCLUSION:Restriction of fluid intake in PAH patients was highly effective and associated with significantly longer TTCW. Further evaluation of fluid restriction in PAH patients is needed in larger studies.

General measures and special conditions were addressed by the ninth task force at the 7th World Symposium on Pulmonary Hypertension. It focused primarily on the patient perspective, general and supportive measures, and challenging patient conditions. Regarding the latter, particular attention was paid to perioperative care, management during pregnancy, medication adherence, palliative care, and the sinfluence of climate on the disease. Furthermore, this paper addresses several additional topics that fall within this context but were not addressed at the World Symposium, such as nutrition in pulmonary hypertension, travel, and the use of cardiovascular drugs.

Obesity or underweight can complicate and aggravate symptoms and progression of right heart failure in patients with pulmonary arterial hypertension (PAH). This study investigates the influence of different body mass index (BMI) categories on right heart function and outcome in PAH patients. In this cross-sectional study with survival follow-up (mean follow-up 3.1 ± 2.6 years, median 2.7 years), clinical measures such as WHO-functional class and invasively measured hemodynamic parameters at initial diagnosis of PAH were compared between different BMI groups. Out of 2055 data sets, 755 patients with PAH (62.5

Beim 7. Weltsymposium für pulmonale Hypertonie (WSPH) in 2024 widmete sich eine Arbeitsgruppe der Risikostratifizierung und den Behandlungszielen von Patient*innen mit pulmonalarterieller Hypertonie (PAH) und eine der Lungentransplantation und überbrückenden Maßnahmen. Diese Arbeit fasst die jeweiligen Ergebnisse prägnant zusammen. Die ursprünglichen Publikationen der WSPH-Arbeitsgruppen 7 und 8 wurden ins Deutsche übersetzt und gekürzt. Die Risikostratifizierung hilft bei der Vorhersage des Krankheitsverlaufs und der Behandlungssteuerung von PAH-Patient*innen. Die meisten Stratifizierungsmodelle beinhalten die nichtinvasiven Parameter funktionelle WHO(Weltgesundheitsorganisation)-Klasse, 6‑Minuten-Gehstrecke und natriuretische Peptide. Zusätzliche Parameter z. B. aus der invasiven Hämodynamik oder aus der kardialen Bildgebung könnten die Aussagekraft verbessern. Bei Hochrisikopatient*innen trotz maximaler Therapie sollte eine Lungentransplantation in Betracht gezogen werden. Die Thematik sollte daher frühzeitig mit den Patient*innen besprochen werden, um eine Evaluation und ggf. Listung zu ermöglichen. Unterstützungstechniken wie eine venoarterielle extrakorporale Membranoxygenierung können präoperativ die Wartezeit auf ein passendes Organ überbrücken und postoperativ eine schonendere Herzadaptation ermöglichen. Die Risikostratifizierung wurde kontinuierlich verbessert, um eine bestmögliche Prädiktion zu liefern. Dennoch werden nicht alle Patient*innen-Kollektive gut genug abgebildet, und es bedarf weiterer Optimierung. Auch die überbrückenden Maßnahmen bis zu einer Lungentransplantation werden in Expertenzentren zunehmend verbessert, um ein Versterben auf der Warteliste zu einer Transplantation zu vermeiden.

Background Exercise-transthoracic Doppler echocardiography (Ex-TTE) determination of mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope may offer key diagnostic and prognostic information in cardiorespiratory diseases. However, its applicability and reliability in routine clinical practice remain to be established. Herein, the aim of the present study was to apply a machine learning (ML) model to predict abnormal exercise TTE-derived mPAP/CO slope (>3 mmHg/L·min) in individuals at risk of pulmonary hypertension (PH), based only on clinical and resting TTE parameters. Methods The study population (221 healthy adults and 196 patients with connective tissue disease) was grouped according to mPAP/CO slope ≤3 vs. >3 mmHg/L·min (n=222 and n=195, respectively). Three different ML models (Elastic Net-Regularized Generalized Linear Model, Classification and Regression Tree, LogitBoost) were trained on resting clinical and TTE parameters to predict mPAP/CO slope >3 mmHg/L·min. Data were split into training/test sets to evaluate performance. The model with the highest area under the curve (AUC) on the test set was selected. Results The Elastic Net model achieved the best performance (AUC=0.92). Lower tricuspid annular plane systolic excursion/systolic PAP ratio, female sex, and smaller left ventricular outflow tract diameter were the key features predicting TTE-derived mPAP/CO slope >3 mmHg/L·min. Conclusions An ML algorithm using resting clinical and TTE parameters can effectively predict exercise TTE-derived mPAP/CO slope >3 mmHg/L·min, supporting its use as a noninvasive tool to identify individuals at risk of exercise PH.

Allgemeine Therapiemaßnahmen und besondere Situationen wurden bei der 7. Weltkonferenz für Pulmonale Hypertonie von der neunten Taskforce bearbeitet. Sie konzentrierte sich v. a. auf die Patient*innenperspektive, allgemeine und supportive Maßnahmen und bei Patient*innen bestehende herausfordernde Bedingungen. Bei letzteren werden insbesondere die perioperative Versorgung, das Management während der Schwangerschaft, Medikamentenadhärenz, Palliativversorgung und der Einfluss des Klimas auf die Erkrankung beleuchtet. Darüber hinaus werden in dieser Arbeit einige Themen zusätzlich angesprochen, die in diesen Kontext fallen, jedoch nicht bei der Weltkonferenz Berücksichtigung fanden, wie z. B. Ernährung bei pulmonaler Hypertonie, Reisen und Einsatz kardiovaskulärer Medikamente.