Chan, Stephen Y.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

Abstract Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

AbstractThe Pulmonary Vascular Research Institute GoDeep meta‐registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta‐registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty‐nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface‐based automated retrospective and prospective data transfer, GoDeep aims to provide in‐depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

Abstract The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.