Risk and Resilience in Pulmonary Arterial Hypertension and Genetically Susceptible Individuals

ABSTRACT Pulmonary arterial hypertension (PAH) is an orphan disease with a delayed diagnosis and markedly elevated mortality from right heart failure. Despite nearly a dozen FDA-approved drugs for PAH, median survival is only seven years. All approved therapies target one of three vasodilatory pathways, and none are disease

modifying. This application has two objectives: 1) Understand dynamic and static relationships between molecular markers and PAH progression and resilience; 2) Identify molecular features of PAH risk and resilience in individuals harboring a PAH-causing mutation. It is unknown why some at risk individuals develop

PAH and others do not. BMPR2 mutations are present in about 30% of patients with PAH but clinical penetrance is only 20%. Unaffected BMPR2 mutation carriers (UMCs) are a unique and understudied population that may also provide clues to disease trajectory in patients with clinical PAH. Longitudinal natural

history studies with molecular profiling in PAH are lacking. Most molecular profiling studies in PAH are cross- sectional which limits understanding of how disease progression and disease markers relate over time. We propose a strategy of dense clinical and molecular phenotyping at multiple timepoints to overcome inferential

limitations of cross-sectional studies. This application will leverage the clinical and research infrastructure built at Vanderbilt over the past 35-years in our study of PAH patients. The investigators share an extensive published record of recruiting patients with this rare disease and related UMCs. We hypothesize that a

comprehensive understanding of risk and resilience over time in patients and genetically susceptible individuals will provide insight into disease severity and identify novel therapeutic targets in patients with PAH. Aim 1 will identify static and dynamic molecular features of disease progression and resilience. 1a: Perform

serial clinical, proteomic, and gene expression profiling in HPAH, IPAH, and healthy controls 3 times over 4-years. Bioinformatic and network medicine analyses will identify proteins and RNAs associated with changes in clinical outcomes, functional capacity, and RV function in the parent cohort and two external validation cohorts.

1b: Test whether adding molecular risk/resilience markers will improve the performance of a widely used PAH risk prediction tool (REVEAL 2.0 Risk Score). Aim 2 will identify the clinical and molecular factors that promote resilience and susceptibility to PAH in a longitudinal cohort of UMCs. UMCs will undergo serial clinical and

molecular phenotyping as in Aim 1. Proteins/genes that mirror PAH are “risk factors” and those that mirror a healthy population are “resilience factors”. Explanatory models will be developed and tested in validation cohorts. We will test UMC risk and resilience features for associations with clinical outcomes in PAH patients

and risk prediction performance. These studies will identify signatures of risk and resilience to PAH progression and penetrance, offering an initial step toward personalizing care and surveillance guided by biologic data.