Risk and Resilience in Pulmonary Arterial Hypertension and Genetically Susceptible Individuals

NCT ID: NCT05584722

Last Updated: 2025-02-19

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 150 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-11-01
• Study Completion Date: 2026-08-31

Brief Summary

Pulmonary arterial hypertension (PAH) is a severe disease with a delayed diagnosis and markedly elevated mortality. High-risk populations, such as those with known genetic defects, provide a unique opportunity to determine the features of susceptibility and resilience to PAH. This proposal will fundamentally overturn the prevailing understanding of PAH by creating molecularly-driven signatures of susceptibility and resilience, provide novel insight into disease severity, and potentially identify new therapeutic targets.

Funding Source - FDA OOPD

Detailed Description

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 study 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. The Investigators 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. The Investigators 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. The Investigators 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.

Conditions

Idiopathic Pulmonary Arterial Hypertension; Heritable Pulmonary Arterial Hypertension; Unaffected Mutation Carriers: Healthy Participants With a Known BMPR2 Gene Mutation and Normal Pulmonary Pressure and RV Function on Echo; Healthy Individuals With no Cardiopulmonary Disease

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Idiopathic or Heritable Pulmonary Arterial Hypertension

Patients diagnosed with pulmonary arterial hypertension, either idiopathic or heritable, defined according to standard criteria.

No interventions assigned to this group

Unaffected Mutation Carriers

Healthy participants with a known BMPR2 gene mutation and normal pulmonary pressure and RV function on echo.

No interventions assigned to this group

Healthy Controls

Healthy individuals without cardiopulmonary disease

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Children and Adults, aged 15 - 80
• Diagnosed with idiopathic or heritable, pulmonary arterial hypertension (PAH), defined according to standard criteria
• Unaffected Mutation Carriers: Healthy participants with a known BMPR2 gene mutation and normal pulmonary pressure and RV function on echo
• Healthy Controls: Healthy individuals without cardiopulmonary disease.
• WHO functional class I-III
• Stable PAH-specific medication regimen for three months prior to enrollment. Subjects with only a single diuretic adjustment in the prior three months will be included. Adjustments in IV prostacyclin for side effect management are allowed.

Exclusion Criteria

• Prohibited from normal activity due to wheelchair bound status, bed bound status, reliance on a cane/walker, activity-limiting angina, activity-limiting osteoarthritis, or other condition that limits activity.
• Pregnancy
• Diagnosis of PAH etiology other than idiopathic, heritable
• Functional class IV heart failure
• Requirement of > 2 diuretic adjustment in the prior three months.

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Anna Hemnes

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Evan Brittain, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt Medical Center

Anna Hemnes, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt Medical Center

Eric Austin, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kelly Burke, RN

Role: CONTACT

kelly.burke@vumc.org

(615) 343-4682

Alisha Lindsey, RT

Role: CONTACT

alisha.lindsey@vumc.org

(615) 343-4682

Facility Contacts

Kelly Burke, RN

Role: primary

kelly.burke@vumc.org

Other Identifiers

1R01FD007627

Identifier Type: FDA

Identifier Source: secondary_id

View Link

221437

Identifier Type: -

Identifier Source: org_study_id