Open research questions in Pulmonary Hypertension Research and Treatments

What the literature leaves open

• While this pathologic cycle is well characterized in PH patients, there are few data on longitudinal changes in the right ventricle in patients with PH and CKD.

  Pulmonary Hypertension, Right Ventricular Remodeling and Outcomes in Chronic Kidney Disease · 2026 · DOI

• The pathophysiology of PH in CKD has not been studied in detail primarily because studies incorporating right heart catheterization, the gold-standard test for diagnosing and phenotyping PH, are rare and therefore data regarding the hemodynamic phenotypes of PH in CKD patients are sparse.

  Pulmonary Hypertension, Right Ventricular Remodeling and Outcomes in Chronic Kidney Disease · 2026 · DOI

• The {beta}3-adrenergic receptor ({beta}3-AR) has been implicated in cardiovascular regulation and cardioprotective mechanisms; however, its role in pulmonary vascular disease remains poorly understood.

  Endothelial β3-Adrenergic Receptor activation prevents pulmonary hypertension · 2026 · DOI

• BackgroundPulmonary arterial hypertension (PAH) is driven by maladaptive endothelial remodeling, but the transcriptional regulators that couple proliferative stress to arterialized endothelial states remain incompletely defined.

  E2F1 Drives Endothelial Arterial Programming in Pulmonary Arterial Hypertension · 2026 · DOI

• E2F transcription factor 1 (E2F1) is classically viewed as a cell-cycle regulator; whether E2F1 functions as a disease-driving node that promotes endothelial arterial programming in PAH remains unknown.

  E2F1 Drives Endothelial Arterial Programming in Pulmonary Arterial Hypertension · 2026 · DOI

• 28 Future research should focus on long-term registry studies to assess durability of treat- ment effects and impact on survival, larger multicenter studies to enable etiology-specific and age-stratified analy- ses, and investigation of biomarkers that predict treatment Macitentan in Pediatric PAHAdvance Publication 8 response to facilitate personalized therapeutic approaches. Study Limitations The main limitations of this study are the open-label, sin- gle-arm design, which precluded comparisons between macitentan and SoC, and the relatively small sample size. Further studies with larger sample size and a comparative design are warranted to further characterize the effect of maciten- tan in children with PAH.

  Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients With Pulmonary Arterial Hypertension ― Prospective, Multicenter, Open-Label Study ― · 2026 · DOI

• Rationale: Pulmonary artery (PA) enlargement is a non-invasive imaging biomarker associated with pulmonary hypertension and mortality in COPD; however, its genetic determinants remain incompletely understood.

  Genetic Determinants of Pulmonary Artery Size in over 50,000 Subjects with and without COPD · 2026 · DOI

• Pulmonary microvascular endothelial cell (PMVEC) dysfunction promotes capillary rarefaction and vascular remodeling, but epigenetic mechanisms after neonatal hyperoxia are poorly defined.

  Endothelial Baf60c in BPD-Associated Pulmonary Hypertension · 2026 · DOI

• Baf60c (SMARCD3), a SWI/SNF subunit supporting vascular homeostasis, and Smarcc2 (BAF170), a PBAF scaffold subunit linked to proliferative signaling, have not been studied together in BPD-PH.

  Endothelial Baf60c in BPD-Associated Pulmonary Hypertension · 2026 · DOI

• BackgroundPulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear.

  Metabolomic Network Analysis Reveals Reorganization of Lipid and Steroid Programs Linked to Right Ventricular-Pulmonary Vascular Function in Pulmonary Hypertension · 2026 · DOI

• Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated.

  Resolving Diagnostic Discordance in Group 2 Pulmonary Hypertension Through Staged Physiologic Testing: Insights From PVDOMICS · 2026 · DOI

• 5 “PAH with features of venous/capillary involvement” (formerly Pulmonary Veno-Occlusive Disease or Pulmonary Capillary Hemangiomatosis, now collectively termed PVOD/PCH) remain underrecognized, develop serious complications from usual PAH therapy titrations, and suffer high mortality awaiting necessary lung transplant.

  Identification of Pulmonary Arterial Hypertension Patients with Venous or Capillary Involvement · 2026 · DOI

• Whether high-flow shunting induces branch-selective unfolded protein response (UPR) activation and endoplasmic reticulum (ER) structural adaptation in pulmonary vascular smooth muscle remains incompletely defined.

  Dissociation of UPR signaling and ER ultrastructure during 4-PBA therapy in shunt-driven pulmonary hypertension · 2026 · DOI

• What Is Relevance?Cognitive impairment is common but underrecognized in CTEPH, BPA now addresses both cardiopulmonary and cognitive dysfunction, improving quality of life beyond hemodynamic recovery.

  BPA Improved the Cognitive Dysfunction of Patients with CTEPH · 2026 · DOI

• Its incidence varies widely across regions: in Europe and North America, systemic sclerosis-associated PAH (SSc-PAH) predominates, whereas in China, systemic lupus erythematosus-associated PAH (SLE-PAH) and Sjögren’s syndrome-associated PAH (SS-PAH) are more common.

  Research advances in connective tissue disease-associated pulmonary arterial hypertension with an emphasis on the Chinese population · 2026 · DOI

• Age-related stiffening of large arteries is a predictor of cardiovascular morbidity and mortality, yet how pulmonary vascular stiffening integrates with right ventricular (RV) and lung functional decline and how best to quantify biological cardiopulmonary aging remains unclear.

  Biological Aging of the Cardiopulmonary System · 2026 · DOI

• This study contains many limitations. First, death certifi- cate data might be subject to misclassification of PVD or IHD as the underlying cause, as it is based on ICD codes. Second, the CDC WONDER database lacks clinical infor- mation, including comorbidities, risk factors, treatment history, laboratory parameters, and genetic findings, which limit deeper analysis. Moreover, a large number of deaths occurred at home or in unspecified locations, hence making the confirmation of diagnosis uncertain. Data for some of the racial groups were excluded because some of the races had suppressed data or crude mortality rates (CMRs) with zero standard error; as a result, their inclusion in the Join- point regression analysis was not possible. Additionally, the CDC WONDER database provides crude mortality rates when classified by age group or place of death, rather than age-adjusted mortality rates. Finally, sample size calcula- tion or justification could not be performed, as this study was retrospective and the number of fatalities available was fixed within the CDC WONDER dataset.

  Two decades of pulmonary vascular disease and ischemic heart disease mortality in the united states: A longitudinal analysis using CDC WONDER (1999–2020) · 2026 · DOI

• Future studies should include larger prospective multicenter cohorts to validate the prognostic significance of invasive hemodynamic parameters in advanced heart failure. Broader recruitment would improve generalizability and allow more robust adjusted analyses to determine whether CO, CI, and PAPi remain associated with adverse outcomes after accounting for clinical confounders. Serial hemodynamic assessment, integrated with echocardiographic and laboratory markers, may also provide a more comprehensive strategy for risk stratification. In the Indonesian setting, expanding local data on RHC may help refine its role in identifying high-risk patients with advanced heart failure and in guiding clinical decision-making.

  Right Heart Catheterization Hemodynamic Parameters and Cardiovascular Adverse Events in Advanced Heart Failure: A Retrospective Cohort Study · 2026 · DOI

• EVIDENCE PAH UK was a haemodynamic database. Although a wealth of data, echo parameters were supple- mentary. Measurements were taken from reports and not raw data and re-analysis of echo images. As result although we focus on doppler measurements, additional supporting echo metrics are lacking in detail in sufficient numbers of patients to be analysed. As a result, there was missingness in the data set. Focused echo regis- tries are important where newer multiparameter such as right ventricular free wall longitudinal strain (RVFWLS) and right ventricular fractional area of change (RVFAC) as reviewed IMPULSE [22] (IRAS Project ID: 323768) show great promise and maybe a more sensitive marker compared to TAPSE. RVFWLS/sPAP as a marker of RV coupling has also been found to be more powerful com- pared to other metrics [23]. The increased sensitivity may improve detection at mild elevations of haemodynamics, compared to conventional metrics. Although we have excluded patients who do not have a TRV measurement, not having a TRV does not mean no PH. Even in the presence of PH around 15% have no Karia et al. Echo Research & Practice (2026) 13:20 measurable TRV [22]. Supplementary table 3, shows echo metrics where no TRV was available. Guidelines have also changed over time. As a result, we are applying new guidelines to retrospective data, where referral patterns may have differed. We have also bet- ter standardised PH protocols. An example of this RAP, which used to be reported as a range, reporting has sub- sequently standardised. Chamber size, such as LA/RA, has changed over time from diameter, area and volumes. As a result in this data set which spans between 2009 and 2017, there are various ways of reporting same variables. Although there are methods to make this comparable, makes it difficult to compare more up to date measures/ quantitative measures. A key limitation of our study is that echocardiogra- phy and right heart catheterisation were not performed simultaneously. Echocardiographic assessments were included if conducted within one year prior to, or within three months following, catheterisation. Although we ensured no new targeted therapies had been initiated during this interval, this temporal separation may have introduced variability in haemodynamic and echocardio- graphic measurements. By default, patients will have been deemed high enough risk of PH to undergo catheterisation even where the echo parameters were reassuring. Therefor we are slightly biased towards a higher clinical suspicion of PH in this study.

  Significance of echocardiographic metrics including TRV and TAPSE/SPAP in mild haemodynamic pulmonary hypertension – data from EVIDENCE-PAH UK · 2026 · DOI

• The study focused on a cross-sectional cohort, includ- ing controls and patients with established PH defined by the pre-2022 criterion (mean pulmonary arterial pressure > 25 mmHg). Therefore, the study does not address how the updated definition may affect diagnos- tic interpretation in patients with mild PH (mPAP 20–25 mmHg). Our controls also reflect more active individu- als in the San Francisco Bay area, which could have led to a higher prevalence of RVE in our healthy cohort. The analysis, however, reveals the importance of not carrying forward the previous definition. In conclusion, we quantified the differences between existing definitions of RV transverse diameters and dem- onstrated their implications for assessing RV size, hemo- dynamics, and clinical outcomes in PAH. Although the 2025 ASE guidelines have suggested changing the RV diameter definition for better standardization, our find- ings support the use of maximal basal and mid-transverse diameters using anatomically consistent approaches, when feasible, guided by the RV’s non-linear centerline.

  Impact of guideline definitions on right ventricular diameter in echocardiography: an automated analysis in controls and patients with pulmonary hypertension · 2026 · DOI

• Prostacyclin—Inhaled PERFECT Phase 3 RCT, PH-COPD confirmed 12 weeks ↑ Adverse events, ↓ Early termination, small treprostinil (2024) cross-over study (terminated 6MWD N, heterogeneous early) population PERFECT— Subgroup, crosssPAP >40 mmHg, 12 weeks Suggestion of benefit Exploratory, nonpost hoc over study FEV1 > 40% (terminated early) planned Bajwa et al.

  Prevalence, pathogenesis, and clinical impact of pulmonary hypertension associated with chronic obstructive pulmonary disease · 2026 · DOI

• The paper states that PH classification must incorporate deep phenotyping with genetic information and advanced imaging alongside molecular profiling, but does not detail which imaging modalities, genetic variants, or integration algorithms should be used to combine clinical, imaging, genetic, and proteomic data for defining the proposed new PH taxonomy.

  Personalized Medicine for Pulmonary Hypertension: · 2021 · DOI

• The paper proposes adopting liquid biopsies and multiplex proteomic assays as alternatives to tissue biopsies for identifying druggable pathologic pathways in individual PH patients, but does not specify the optimal panel composition, assay standardization protocols, or threshold cutoffs needed for clinical translation of these molecular signatures into mechanism-based therapeutic selection.

  Personalized Medicine for Pulmonary Hypertension: · 2021 · DOI

• While PVDOMICS aims to generate new pulmonary vascular disease ontologies through machine learning and unbiased network analyses of combined clinical and 'omic' data, the paper does not specify validation strategies or independent datasets required to confirm that consensus clustering-derived patient subgroups will translate to reproducible therapeutic response patterns.

  Personalized Medicine for Pulmonary Hypertension: · 2021 · DOI

• The complement alternative pathway was unmasked in some PAH patients through network analysis of a proteome dataset, but the extent to which complement pathway dysregulation occurs across other PH presentations (Groups 2-5) requires investigation before complement C5a inhibitor trials can be biomarker-stratified across the broader PH population.

  Personalized Medicine for Pulmonary Hypertension: · 2021 · DOI

Most-cited papers in Pulmonary Hypertension Research and Treatments

• Definition, classification and diagnosis of pulmonary hypertension · European Respiratory Journal · 2024 · 374 citations
• Global, regional, and national burden of pulmonary arterial hypertension, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021 · The Lancet Respiratory Medicine · 2024 · 102 citations
• Worldwide CTEPH Registry: Long-Term Outcomes With Pulmonary Endarterectomy, Balloon Pulmonary Angioplasty, and Medical Therapy · Circulation · 2024 · 83 citations
• Cardinality Quantifiers and Choice Principles. · Reports on Mathematical Logic · 1991 · 73 citations
• 2024 Clinical practice guidelines for Pulmonary hypertension, including chronic thromboembolic pulmonary hypertension · Russian Journal of Cardiology · 2024 · 53 citations
• Depletion of Alveolar Macrophages Attenuates Hypoxic Pulmonary Hypertension but not Hypoxia-Induced Increase in Serum Concentration of MCP-1 · Physiological Research · 2016 · 38 citations
• Phenotype and function of macrophage polarization in monocrotaline-induced pulmonary arterial hypertension rat model · Physiological Research · 2021 · 22 citations
• The early detection of pulmonary hypertension · Deutsches Ärzteblatt international · 2023 · 14 citations
• Personalized Medicine for Pulmonary Hypertension: · Clinics in Chest Medicine · 2021 · 10 citations
• Recent advances in the pharmacotherapy of pulmonary hypertension: practical considerations · Kardiologia Polska · 2021 · 9 citations

Most recent work

• Sotatercept for Combined Post- and Precapillary Pulmonary Hypertension Associated With Heart Failure: Results From the Phase 2, Randomized, Placebo-Controlled CADENCE Study · Circulation · 2026
• ALDOB K87 lactylation drives mitochondrial fission and metabolic reprogramming in pulmonary hypertension · Communications Biology · 2026
• Metabolomics of Right Ventricular Function in Pulmonary Hypertension · Circulation Research · 2026
• EBF1 controls an embryonic artery-forming niche that reactivates in pulmonary arterial hypertension · bioRxiv · 2026
• Biological Aging of the Cardiopulmonary System · bioRxiv · 2026
• Subamnex Ameliorates Hypoxia-Induced Pulmonary Arterial Hypertension through Modulation of the STAT3/p-STAT3 Pathway · Journal of Medicinal Chemistry · 2026
• HYAL3 as a therapeutic target for pulmonary arterial Hypertension–Cardiomyopathy comorbidity: an integrative analysis combined with machine learning and SHAP value interpretation · Frontiers in Pharmacology · 2026
• Mechanistic studies of molecular networks associated with pulmonary hypertension explored by combined transcriptome analysis of Project-methylation · Clinical Epigenetics · 2026
• Novel KCNK3 variant in a child with pulmonary arterial hypertension · Hereditas · 2026
• Right Ventricular Strain Secondary to Tumor-Induced Pulmonary Artery Obstruction: An Incidental ¹⁸ F-FDG PET/CT Finding in Small Cell Pancoast Tumor · Indian Journal of Nuclear Medicine · 2026

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