Critical Care Medicine Department
Intramural NIH Pulmonary Arterial Hypertension (PAH) Program
- Basic Science Research
- Pre-Clinical Research
- Translational Clinical Research
- Travel, Lodging and Compensation
- Intramural NIH Sponsored IRB Approved Active PAH Protocols
- Opportunities for Intramural – Extramural Collaborative Research at the NIH CC
The NIH intramural program is well suited to studying WHO group 1 pulmonary hypertension. Intramural NIH has a long history of recruiting patients with rare disorders through its ability to target wide geographic areas. At the heart of the campus, the Clinical Center (CC) provides a warm and supportive state-of-the-art hospital providing quality medical care for all patients who qualify for protocols. The Critical Care Medicine Department (CCMD) has the medical expertise, basic science laboratories, and pre-clinical and clinical resources necessary to support a multidisciplinary PAH translational research program.
PAH is characterized by vascular dysfunction, inflammation, aberrant angiogenesis, altered cellular metabolism and a pro-proliferative state and thus is of interest to and can potentially utilize the expertise of multiple NIH institutes. The intramural program also has advanced resources that can be focused on PAH; Cell Processing Section, Functional Genomics Facility, and the Center for Human Immunology. There are also specialized clinical applications at the NIH CC such as advanced magnetic resonance imaging (MRI) sequences, low dose radiation cardiac computer tomography (CT) and hemodynamic assessments that include real-time MRI.
The intramural NIH CC, CCMD, PAH program is an integrated bench-to-bedside-to-bench effort consisting of a multidisciplinary medical staff with expertise in cardiovascular diseases, pulmonary medicine, infectious diseases, and critical care medicine as well as a regulatory and research nursing support staff with extensive experience in assuring compliance with clinical protocols while maintaining the highest standards of clinical care. The NIH PAH program has the ability to manage PAH patients with state-of-the-art therapy and is also conducting basic science, pre-clinical, and clinical PAH research into pulmonary vascular inflammation in PAH.
The CCMD Vascular Biology component of the PAH program areas of focus include: 1) nuclear receptor signaling and regulation of inflammation; 2) molecular mechanisms that underlie endothelial dysfunction and inflammation in PAH; and 3) exploration of potential therapeutic targets for arresting or reversing pathologic vascular remodeling in PAH using in vitro models and cells obtained from patients.
Aldosterone-mediated mineralocorticoid receptor (MR) activation directly contributes to endothelial dysfunction, pathological pulmonary vascular remodeling and RV dysfunction in PAH. Spironolactone, a MR antagonist, has been shown to improve endothelial function in a variety of cardiovascular diseases. In addition to the beneficial effects of MR antagonists on endothelial function, our group is exploring the mechanisms responsible for the anti-inflammatory properties of spironolactone.
In vitro profiling of pulmonary artery endothelial cells with heterogeneous PAH-associated loss-of-function molecular defects (e.g. bone morphogenetic protein type II receptor, caveolin-1, SMAD8/9, and EGLN1) will be used to develop a comprehensive picture of pathogenic mechanisms that can be exploited therapeutically. The comparative biology of seemingly unrelated molecular defects may lead to individualized and possibly universal approaches for arresting or even reversing pathologic vascular remodeling.
The CCMD animal laboratory has decades of experience developing small and large animal models to evaluate disease pathogenesis and novel therapeutic strategies in critical illness. With expertise in cardiovascular physiology, hemodynamic monitoring, echocardiography, and trial design, CCMD's animal lab is well equipped to convert cellular and molecular observations into in vivo studies of pulmonary vascular disease. For example, building on our in vitro work, the effects of spironolactone on inflammation will be directly compared to eplerenone in the SU-5416/hypoxia/normoxia rat model of PAH.
In the Natural History PAH Study (Natural-PAH) patients are thoroughly characterized by echocardiogram, 6-minute walk, cardiopulmonary stress testing, pulmonary function testing, cardiac CT, advanced MRI techniques, gene expression profiling, and serum biomarkers. The collective data will be used to investigate the ability of circulating markers of vascular inflammation, gene expression profiles, and high-resolution cardiac CT and MRI to accurately stage severity of disease and/or predict clinically relevant outcomes. In addition, providing a detailed characterization of the temporal evolution of vascular inflammation in PAH and its impact on RV and pulmonary vascular function could add prognostic value to traditional measures of disease severity and suggest novel therapeutic targets for future research.
In vitro studies done by the Vascular Biology group of our PAH program have elucidated a novel MR independent anti-inflammatory effect of spironolactone. The CCMD PAH program is investigating the role of initiating therapy with spironolactone at an earlier stage of disease in patients with PAH to determine if spironolactone could provide additional benefits through anti-inflammatory effects and improvements in pulmonary artery endothelial function. Patients with PAH are being enrolled in the Spironolactone Randomized Interventional Trial (SPIRIT-PAH). SPIRIT-PAH is a phase 1-2 randomized double blinded, placebo-controlled six-month study of early treatment with spironolactone. The SPIRIT-PAH trial investigates spironolactone's safety, tolerability and efficacy.
The cost of study testing is covered by the protocols and participants are compensated for their time. For patients living and traveling greater than 50 miles to the NIH CC we also provide partial travel compensation and if available the NIH Safra Family Lodge is free of charge to the patient. In addition, both downtown Bethesda and Rockville have numerous hotels and are less than a 10- or 15–minute drive from the NIH Campus, respectively. The NIH campus is also accessible by Metro. The Red Line Medical Center Station is located at the South Drive gates of NIH (357 KB).
Adrien Mazer, MD
Other Critical Care Services
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This page last updated on 07/27/2017