Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report

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.

Keywords: Pulmonary Vascular Disease Phenomics; master protocol; precision medicine; pulmonary hypertension; pulmonary vascular disease.

Figure 1.

Genomic decision tree to differentiate vasodilator-responsive pulmonary arterial hypertension (VR-PAH) from vasodilator-nonresponsive pulmonary arterial hypertension (VN-PAH). The figure shows an example of a decision tree based on the primary gene RHOQ with a secondary gene, TPD52. RHOQ encodes a cytoskeletal protein involved in insulin-mediated signaling, TPD52 encodes a protein in vesicle-mediated transfer, and DSG2 is a desmosomal cadherin involved in Wnt/B-catenin signaling. Numbers shown within the tree are for the performance of the tree in the test cohort, and in the upper right is the performance in the validation cohort. This genomic decision tree correctly identified five of five vasodilator-responsive patients in the validation cohort. Adapted by permission from Reference .

Figure 2.

Schematic approach to acquire basic and phenotypic information on multiple individuals and groups of patients with pulmonary vascular disease (PVD). This process should lead to insights and therapies that are more directed at specific mechanisms of disease than is now possible. The omic plan in Pulmonary Vascular Disease Phenomics includes genomic DNA, mRNA expression, proteomics, metabolic variation (especially with exercise and with right ventricular energetics), coagulation profiles, endothelial cell function, and lung and cellular imaging. Data will be linked agnostically to cardiopulmonary function data and to patient clinical features and medical history. Comparators will include normal control subjects and disease control subjects, such as patients with emphysema or pulmonary fibrosis (22).

Figure 3.

Phenomapping for novel classification of heart failure with preserved ejection fraction. (A) Phenotype heat map (phenomap) of heart failure with preserved ejection fraction. Columns represent individual study participants; rows represent individual phenotypes. Red indicates increased value of a phenotype; blue indicates decreased value of a phenotype. (B) Survival free of cardiovascular (CV) hospitalization or death stratified by phenogroup. Reprinted by permission from Reference .

Figure 4.

Selective adrenomedullin receptor ligand as an imaging modality of the pulmonary vascular endothelium. (A) Molecular single-photon emission computed tomography imaging of the pulmonary circulation with 99mTc-PulmoBind, a selective adrenomedullin receptor ligand, in a healthy human and in subjects with pulmonary hypertension. (B) Intense staining (red) of the adrenomedullin receptor in human lung capillaries. The star indicates the alveolar wall with intensively stained capillaries, the open arrow indicates slightly positive alveolar macrophages, and the solid arrow indicates the septal wall. CTEPH = chronic thromboembolic pulmonary hypertension; PAH = pulmonary arterial hypertension. Adapted by permission from References and .

Figure 5.

Lung fluorodeoxyglucose (FDG) uptake in patients with pulmonary arterial hypertension (PAH) are shown in comparison to normal control patients. (A) ¹⁸FDG uptake in the idiopathic PAH (IPAH) patient group was increased compared with control subjects. (B) Two-tissue compartment model analysis demonstrated a significantly higher k₃ in lungs of patients with IPAH than in control subjects, consistent with increased intracellular glucose metabolism. (C, a) Computed tomographic thorax image (transverse view). (b) Computed tomographic thresholding to define lungs. (c) Defined region of interest in computed tomographic view of lung parenchyma. (d) Coregistration of region of interest with positron emission tomography image. (e) Representative map of lung parametric FDG score in region of interest. (f) Distribution of voxels with top 25% FDG scores in region of interest. (D) Representative three-dimensional parametric map generated from computed per-voxel FDG scores from a patient with IPAH showing uneven FDG uptake within the lung. CTD = connective tissue disease. Adapted by permission from Reference .