RATIONALE AND OBJECTIVES:Inflammation is associated with all types of pulmonary hypertension (PH), both as a known cause and as a putative confounder. The most common marker of inflammation, C-reactive protein (CRP), has not been widely studied in PH. This study set out to clarify if CRP informs clinical endotyping and outcomes. METHODS:Time-series clustering of longitudinal CRP concentrations was employed. Clinical differences between clusters were validated in three independent U.K./international cohorts using clinical cutoff values (n = 10,301; U.K. cohort, ASPIRE and FDA cohort). Associations were analyzed with functional and mortality outcomes by linear and Cox regression models including all causes of PH (groups 1-5). To add mechanistic insight, multiomics were interrogated from associated previously published arrays. MEASUREMENTS AND MAIN RESULTS:Patients were segregated into two stable CRP clusters (median CRP, 2 vs. 6.5 mg/L), with the high cluster exhibiting significantly higher body mass index (BMI) (difference between medians [DBM], 5.4 kg/m2), higher right atrial pressure (DBM, 2 mm Hg), and reduced 6-minute-walk distance (DBM, 55 m). Inflammation was associated with worse survival and comorbidities, higher pulmonary vascular resistance, and smoking status. CRP and BMI were associated with differing inflammatory profiles in proteomic and transcriptomic analyses. Despite the relationship with CRP, higher BMI was associated with improved survival and lower pulmonary vascular resistance and did not negatively affect 6-minute-walk distance treatment-related functional responses. CONCLUSIONS:We establish a relationship between CRP and BMI across all-cause PH, although CRP and BMI are associated with diverging clinical outcomes. Inflammation and obesity are relevant phenotypes for consideration in clinical trial design. Understanding their impacts on outcomes is important for clinical practice.

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.

Introduction The mechanism, frequency and clinical impact of arrhythmias in pulmonary hypertension (PH) are unclear. We sought to clarify the electrophysiological mechanism in PH and correlate with arrhythmia incidence and clinical outcomes. Methods Invasive (n=10) and non-invasive (n=30) electrophysiological mapping techniques determined myocardial conduction velocity, scar burden and atrioventricular (AV) nodal refractoriness, which were then related to cardiac structure and function. Implantable cardiac monitors (ICMs) were implanted into 80 patients with pulmonary arterial hypertension (PAH). Arrhythmia and clinical worsening episodes were prospectively assessed over 186 patient-years follow-up, and features associated with arrhythmia incidence were identified. Two cohorts encompassing all causes of PH (n=564 and n=3348) were interrogated to assess the relationship between defined arrhythmia risk variables and outcomes. Results Right atrial (RA) dilatation was associated with slower conduction velocity (R=0.52, p=0.01) and more prolonged AV nodal refractoriness (R=0.82, p=0.03). In the ICM study, 79 arrhythmia events were noted in 40% of participants. Only RA size was independently associated with significant arrhythmia (HR 1.03, 95% CI 1.01-1.06, p=0.01). Arrhythmia incidence associated with clinical worsening, and 20% of patients received ICM-uncovered targeted arrhythmia treatment. 69% of patients with treated arrhythmia were asymptomatic (median time-to-arrhythmia-detection 7 months). In both longitudinal PH cohorts, right atrial (RA) size was associated with worse survival independent of RA pressure and pulmonary vascular resistance. Interpretation The dominant mechanism associated with disordered cardiac electrophysiology in pulmonary hypertension patients is RA enlargement. RA size was the only significant variable associated with longitudinal arrhythmias in PAH and in two large prospective cohorts with representative populations of all causes of pulmonary hypertension, RA size is predictive of outcomes independent of pulmonary vascular resistance. Randomised trials are needed to clarify if screening and treating arrhythmias in pulmonary hypertension improves outcomes. ### Competing Interest Statement Alex Rothman would like to acknowledge research funding from the Wellcome Trust (206632/Z/17/Z). Fu Siong Ng would like to acknowledge research funding from the British Heart Foundation (RG/F/22/110078 and RE/24/130023). Rob McKenzie-Ross, Robin Condliffe, David Kiely: honoraria from Janssen. Claire Martin: honoraria and consulting fees from Medtronic, Boston Scientific, Biosense Webster. The ASPIRE registry is supported by the National Institute for Health and Care Research (NIHR) Sheffield Biomedical Research Centre (NIHR203321). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.   ### Funding Statement We wish to acknowledge Boston Scientific and Medtronic as funding sources for this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The National Research Ethics Service of the UK gave ethical approval for this work (13/EE/0203) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Introduction The modified World Health Organization (mWHO) classification of maternal risk is used to estimate morbidity and mortality in pregnant women with cardiovascular disease. Despite guidelines advising against pregnancy in the highest risk category (mWHO Class IV), successful outcomes have been achieved in select managed cases with specialised multidisciplinary care. This single-centre study examines pregnancy outcomes in this high-risk group. Methods We conducted a retrospective cohort study of 32 pregnancies in 30 women classified as mWHO Class IV between 2008 and 2022. Maternal demographics, cardiac and obstetric complications, delivery details, neonatal outcomes, and long-term follow-up data were collected and analysed. Results The mean maternal age at delivery was 29.6 ± 5.1 years. Pulmonary arterial hypertension (PAH) and systemic ventricular dysfunction were the most prevalent conditions. Cardiovascular events occurred in 65.6 % of pregnancies, with PAH accounting for the majority. All women delivered via Caesarean section, with 93.7 % under general anaesthesia. Preterm birth occurred in 75 % of cases, and 87 % of neonates required NICU admission. One maternal death occurred in the late postpartum period. At one year, the major adverse cardiovascular event (MACE) rate was 9.3 %. Long-term follow-up revealed three additional maternal deaths. Conclusions Although pregnancy in women with mWHO Class IV disease carries substantial risk, favourable outcomes are achievable in a tertiary centre with a specialised Pregnancy Heart Team. However, the burden of morbidity remains high, reinforcing the need for early counselling, close surveillance, and long-term follow-up in this vulnerable population.

Pulmonary Arterial Hypertension (PAH) is a complex and progressive disease characterized by elevated pulmonary vascular resistance and right heart failure. Current therapies primarily focus on pulmonary vasodilation; however, novel approaches that target the underlying pathophysiological mechanisms—such as TGF-β signalling, epigenetic alterations, growth factors, inflammation, and extracellular matrix remodelling—are promising alternatives for improving treatment outcomes. This is a review of recent advances in the development of innovative therapeutic strategies for PAH.The first section of this paper explores approaches targeting TGF-β signalling, both acting directly on receptors through drugs like Sotatercept and exogenous BMP9, and indirectly, inhibiting the degradation of key receptors, such as BMPR2. Subsequent sections describe treatments that target epigenetic regulators, e.g. poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors and direct BRD4 antagonists, tyrosine kinase inhibitors (Seralutinib), and therapies aimed at inflammation, such as IL-6 inhibitors, CD-20 inhibitors, and monoclonal antibodies that prevent macrophage migration. Finally, strategies that target the serotonin pathway, and other metabolic and hormonal pathways are described.This review includes both preclinical and clinical trial data that support efficacy, safety and the future potential of such therapies. Collectively, these therapeutic approaches can be valuable in treating PAH by targeting multiple aspects of its pathogenesis, potentially resulting in improved clinical outcomes for patients affected by this debilitating, life-limiting condition.

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.

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10(-7)) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10(-4)). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.

Abstract Introduction Pulmonary arterial hypertension (PAH) is characterised by pre-capillary pulmonary vascular remodelling. Imatinib, a tyrosine kinase inhibitor, was the first treatment investigated in PAH patients with the primary aim of targeting vascular remodelling. A Phase 3 study showed that imatinib 400mg daily reduces pulmonary vascular resistance and increases exercise capacity but only 43% of patients continued the drug for 6 months. Concerns about safety prevented regulatory approval. Purpose To identify a safe and tolerated dose of oral Imatinib and evaluate efficacy in the dose range 100-400mg daily. Methods Oral Imatinib was added to the background therapy of 17 patients with PAH; prior intracranial haemorrhage was excluded by cross sectional imaging and none were receiving an anticoagulant. The first patient started on 100mg daily. The next 12 patients were recruited serially at a minimum of 4 week intervals and started on 200mg, 300mg or 400mg, according to a Bayesian adaptive design (Continuous Reassessment Method, CRM). Patients 14-17 were recruited as an extension cohort to better understand the safety and tolerability of the 100mg and 200mg doses. The primary endpoint was safety and tolerability at 4 weeks. Imatinib was continued for up to 24 weeks. Thirteen patients had implanted devices that provided remote daily measurements of cardiopulmonary haemodynamics and heart rate and rhythm and physical activity. Non-invasive measures of systemic blood pressure, weight and oxygen saturations were made remotely. We compared the time-haemodynamic response relationship with that produced by licensed treatments in a similar patient cohort. Results The recommended starting dose from the CRM was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (P<0.01), increased cardiac output (P=0.08) and reduced total pulmonary resistance (TPR, P<0.001, Figure). There was a clear dose-TPR response relationship (r2=0.52, p<0.01). A reduction in TPR was evident within the first week and plateaued at 4-5 weeks. Withdrawal of Imatinib led to an increase to baseline in TPR over 4-5 weeks. This contrasts with a sharp fall in TPR with licensed therapy and rapid increase on treatment withdrawal. There was a small reduction in systemic vascular resistance (P<0.05) with Imatinib that reached plateau before TPR. Conclusions Oral Imatinib 200mg daily is well tolerated and effective as an add-on treatment in PAH. The time course of the initial haemodynamic response and the gradual return to baseline on withdrawal distinguishes Imatinib from licensed treatments and is supportive of a mechanism of action beyond reliance on vasodilation. Remote monitoring enables the safe evaluation of the withdrawal of an investigational drug in patients established on best medical therapy.Figure 1.

Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing.Methods Reference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata.Results 113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was -7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP.Conclusions Sendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling.

[This corrects the article DOI: 10.1016/j.ijcchd.2022.100331.].