Pulmonary hypertension is the elevation in blood pressure in the lungs and includes many diverse etiologies. At Vanderbilt, our main focus has been understanding the rare disease, pulmonary arterial hypertension (PAH) with a focus on idiopathic and heritable forms of this disease. In particular, we have focused on how female sex and metabolic disease may promote development of pulmonary vascular disease. While there is now effective therapies for PAH, these therapies may have significant side effects and are not curative. Thus our mission is to partner with our patients and researchers to perform high quality translational studies that will ultimately lead to a cure of PAH. Please visit our group’s website here: https://www.vumc.org/pah/vanderbilts-pulmonary-hypertension-team-welcomes-you
Pulmonary Arterial Hypertension – Basic Research
Examining the molecular details of how disease develops allows us to develop therapies targeted at the “control nodes” in the pathways that lead to disease. We take the data we learn from patients, and use it to build models that will allow us to examine mechanisms of disease in detail.
One tool we use are cell culture models, using either cells taken from patients to examine how their characteristics are different from those in healthy individuals, or cells genetically engineered to reproduce the mutations found in disease. We grow these cells under conditions which allow us to better replicate conditions found in the body – for instance, pressure and flow, for blood vessel cells, or having them beat, for cells from the heart.
The other tool we use are mouse models. We take a look at the mutations that cause disease in humans, then reproduce those in mice, to get mice that get pulmonary hypertension for exactly the same molecular reasons that humans do. That means that any therapies we develop that work in mice, are more likely to work in humans.
Right now, we’re working on therapies that intervene at several points in the metabolic defects that look key to PAH, as well as looking at the intersection between estrogen and metabolism, and some small molecules that might fix some of the signaling immediately downstream of the mutations that cause disease. We’re also building more sophisticated models of how circulating cells impact the course of disease.
Right Ventricular Dysfunction – Basic Research
While pulmonary vascular disease is the defining etiology of PAH, most patients eventually develop right ventricular (RV) failure which is the ultimate cause of death in the majority of cases. We have a long track record of research in RV failure spanning clinical observations to molecular etiology. Our current work focuses on the role of the thromboxane-prostanoid receptor in RV remodeling and progression to heart failure during PAH and how metabolic disease can promote or cause RV dysfunction.
We have a very active clinical program caring for patients with this disease and are recruiting in several industry- and NIH-sponsored research studies for patients with PAH. Our NIH-funded studies focus on
- How metabolic disease may promote PAH and if reversal of metabolic dysfunction can improve outcomes in PAH,
- Why women are more likely than men to develop PAH and if interventions to disrupt estrogen signaling may improve outcomes in PAH,
- Determining molecular predictors of drug responses in PAH
- Studies with the NIH-funded consortium PVDOMICs to augment and improve the current clinical classification of pulmonary vascular disease.
- Large data approaches to understand epidemiology and clinical phenotypes of pulmonary vascular disease and RV dysfunction.
- Behavioral interventions using mobile health technology to improve exercise capacity and quality of life in PAH
We also participate in industry-sponsored studies to allow access for our patients to promising novel therapeutics.
Currently enrolling trials:
Complexa: This is a multicenter double-blind, placebo-controlled study to evaluate the safety, efficacy and pharmacokinetics of 2 doses of CXA-10 on stable background therapy in 96 subjects 18 to 80 years of age.
Tamoxifen: This clinical research study is aimed at evaluating the safety and effects of Tamoxifen in patients with PAH. Currently, Tamoxifen is an FDA-approved medication used to treat early breast cancer in pre- and postmenopausal women. It will be given as an investigational drug over 6 months in this clinical trial.
Phantom: Multi-center, randomized, double-blind, placebo-controlled, Phase II study of the drug Anastrozole, currently used to treat breast cancer in men and postmenopausal women, for patients with pulmonary arterial hypertension (PAH). Open for patients with WHO Group 1 for a 12-month treatment course.
Precision Med: This is a single center prospective registry of PAH patients initiating PP therapy. The aim of this study will be to collect blood samples for DNA, RNA, proteomics and metabolomics prior to initiation of PP therapy, and again at routine clinic follow-up visits. Patients will also be followed longitudinally to monitor clinical outcomes.
Interventions Against Insulin Resistance in PAH: The primary objective of this study is to determine the impact of two interventions against insulin resistance using blinded trial testing metformin versus placebo and an mHealth intervention (Fitbit) versus usual care for 12 weeks to assess effect on six minute walk and WHO functional class. Enrolling patients with idiopathic, heritable, or drug– or toxin associated pulmonary arterial hypertension (PAH).
L-PVDOMICS: The overall goal of the PVDOMICS network is to perform comprehensive phenotyping (demographic, physiologic, clinical chemistries, and imaging) and endophenotyping (genomic, proteomic, metabolomic, cell and/or tissue based) across the World Health Organization (WHO) classified PH clinical groups 1 through 5 in order to define new subclassifications of patients based on characteristics that are associated with mechanisms of pathogenesis.