Precision Medicine for Pulmonary Vascular Disease: The Future Is Now (2023 Grover Conference Series)

Abstract

Pulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools. Nevertheless, challenges exist in implementing these tools to optimal effect. The 2023 Grover Conference Series reviewed the research landscape to summarize the current state of the art and provide a better understanding of the application of precision medicine to managing pulmonary vascular disease. In particular, the following aspects were discussed: (1) Clinical phenotypes, (2) genetics, (3) epigenetics, (4) biomarker discovery, (5) application of precision biology to clinical trials, (6) the right ventricle (RV), and (7) integrating precision medicine to clinical care. The present review summarizes the content of these discussions and the prospects for the future.

Keywords: biomarker; epigenetics; genomics‐metabolomics‐proteomics; pulmonary hypertension; right ventricle function and dysfunction.

Figure 1

Prevalence of identified genetic factors in pediatric vs. adult PAH. In 443 pediatric and 2628 adult cases of PAH from the Columbia University Irving Medical Center and National Biological Sample and Data Repository for PAH (aka the PAH Biobank) cohorts, de novo and inherited variants were identified in a greater subset of pediatric relative to adult patients. Figure reproduced from “Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension” by CL Welch and WK Chung, Genes (Basel), 2020 Oct 16;11(10):1213 [88].

Figure 2

Classical and emerging biomarkers of PH. Several circulating factors such as cytokines, chemokines, and proteins have been classically identified as putative biomarkers of PH. Recently, the range of these biomarkers has broadened to include new categories for early disease diagnosis and disease stage identification. Among them, extracellular vesicles (EVs), the tissue‐specific microbiome, and circulating factors associated with microbes and metabolites, have emerged in this expanding group of biomarkers. Abbreviations: cAMP = cyclic adenosine monophosphate; HIV = human immunodeficiency virus; PRDX4 = peroxiredoxin‐4; PXDN = peroxidasin homolog; renin, NRP1 = neuropilin‐1; S. mansoni = Schistosoma mansoni; SCFAs = short‐chain fatty acids; SVEP1 = Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1; TSP2 = thrombospondin‐2.

Figure 3

Contributions of “dedifferentiated” endothelial cells to EndoMT for adventitial remodeling. 1. Activated arterial endothelial cells (aAECs) emerge first after Sugen administration, and are characterized by the persistence of differentially expressed genes and a transcriptional profile consistent with growth dysregulation. 2. Classical pericytes give rise to a smooth muscle (SM)‐like pericyte cluster expressing contractile proteins. 3. A dedifferentiated endothelial cell cluster (dDEC) emerges, demonstrating loss of expression of endothelial tight junction genes and upregulation of antigen presenting proteins with reduction in activity of master transcription factors regulating endothelial cell activity. This endothelial‐to‐mesenchymal transition (EndoMT) may contribute to adventitial remodeling.

Figure 4

Top left: Drs. Jack Reeves, future Nobel Laureate Robert Furchgott, and E. Kenneth Weir at the inaugural 1984 Grover Conference [287] Top right: Drs. Weir, Kurt Prins, Sasha Prisco, and Thenappan Thenappan at the 2023 Grover Conference. Bottom: Conference participants at the 2023 Grover Conference.