Pulmonary Hypertension

Coordinator: Dr. Joan Albert Barberà.

Tackling the phenotypic heterogeneity in pulmonary hypertension for an improved and personalized disease management.

Pulmonary hypertension (PH) is a heterogeneous condition that may present as a primary disorder of the pulmonary vasculature (pulmonary arterial hypertension, PAH) or as a consequence of other disease conditions, namely chronic lung diseases (CLD) or pulmonary embolism (PE). Even though PH originates from an impaired endothelium, there is ample heterogeneity in its clinical presentation, not only that it can present as a primary/secondary disorder, but also regarding disease severity, interaction with comorbidities, treatment response and prognosis.

The present strategic project aims to better understand the mechanisms underlying the phenotypic heterogeneity of PH and the reason why only some patients with CLD or PE develop PH, with the final objective to predict, characterize and treat the disease more precisely and effectively.

The project will undertake a structured set of investigations focused on major categories of the PH spectrum. In PAH: a) analyze the transcriptome of pulmonary artery endothelial cell and assess treatment-induced changes; b) evaluate the efficacy and safety of vitamin-D supplementation in a randomized clinical trial; c) analyze the effectiveness of an urban training intervention and identify the mechanisms determining its sustainability; d) analyze the role of the oral and gut microbiome on the nitric oxide pathway.

In CLD: a) identify molecular changes associated with the loss of pulmonary vessels and the development of severe PH; b) characterize phenotypes and endotypes at increased risk of mortality; c) decipher the molecular interactions between pulmonary vessels and the surrounding parenchyma.

In PE: a) identify molecular fingerprints of pulmonary endothelial dysfunction and their association with PH development; b) validate a miRNA panel for predicting the progression to PH; c) analyze the effects of exercise and intermittent hypoxia as contributing factors for PH development.

The project will also undertake transversal actions to a) evaluate the potential of flow-related imaging biomarkers to characterize pulmonary vascular remodeling; b) introduce advanced imaging methods for evaluating metabolic, inflammatory, proliferation and mitochondrial changes; c) evaluate ultrastructural vascular changes by phase-contrast x-ray tomography; d) develop human vascular organoids and 3D-printed experimental models of PH.

The proposal will have high clinical impact as it will provide information on: a) the determinants of treatment response at transcriptomic level; b) the therapeutic potential of vitamin D supplementation; c) the clinical phenotype of patients with CLD candidates to targeted therapy; d) interventions that may modify the progression to PH after PE; e) imaging tools that might reduce the need for invasive procedures; f) new experimental models that might replace the use of animals.