Clinical Features and Outcomes of Patients with Sarcoidosis-associated Pulmonary Hypertension.

Abstract

The presence of pulmonary hypertension (PH) significantly worsens outcomes in patients with advanced sarcoidosis, but its optimal management is unknown. We aimed to characterize a large sarcoidosis-associated pulmonary hypertension (SAPH) cohort to better understand patient characteristics, clinical outcomes, and management strategies including treatment with PH therapies. Patients at Duke University Medical Center with biopsy-proven sarcoidosis and SAPH confirmed by right heart catheterization (RHC) were identified from 1990-2010. Subjects were followed for up to 11 years and assessed for differences by treatment strategy for their SAPH, including those who were not treated with PH-specific therapies. Our primary outcomes of interest were change in 6-minute walk distance (6MWD) and change in N-terminal pro-brain natriuretic peptide (NT-proBNP) by after therapy. We included 95 patients (76% women, 86% African American) with SAPH. Overall, 70% of patients had stage IV pulmonary sarcoidosis, and 77% had functional class III/IV symptoms. Median NT-proBNP value was elevated (910 pg/mL), and right ventricular dysfunction was moderate/severe in 55% of patients. Median values for mean pulmonary artery pressure (49 mmHg) and pulmonary vascular resistance (8.5 Woods units) were consistent with severe pulmonary hypertension. The mortality rate over median 3-year follow-up was 32%. Those who experienced a clinical event and those who did not had similar overall echocardiographic findings, hemodynamics, 6MWD and NT-proBNP at baseline, and unadjusted analysis showed that only follow-up NT-proBNP was associated with all-cause hospitalization or mortality. A sign test to evaluate the difference between NT-Pro-BNP before and after PH therapy produced evidence that a significant difference existed between the median pre- and post-NT-Pro-BNP (-387.0 (IQR: -1373.0-109), p = 0.0495). Use of PH-specific therapy may be helpful in selected patients with SAPH and pre-capillary pulmonary vascular disease. Prospective trials are needed to characterize responses to PH-specific therapy in this subset of patients with SAPH.

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Citation

Published Version (Please cite this version)

10.1038/s41598-019-40030-w

Publication Info

Parikh, Kishan S, Talal Dahhan, Leigh Nicholl, Nicole Ruopp, Gina-Maria Pomann, Terry Fortin, Victor F Tapson, Sudarshan Rajagopal, et al. (2019). Clinical Features and Outcomes of Patients with Sarcoidosis-associated Pulmonary Hypertension. Scientific reports, 9(1). p. 4061. 10.1038/s41598-019-40030-w Retrieved from https://hdl.handle.net/10161/18198.

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Scholars@Duke

Parikh

Kishan S Parikh

Adjunct Associate in the Department of Medicine

Duke University Medical Center
Duke Clinical Research Institute

Dahhan

Talal I Dahhan

Adjunct Associate Professor in the Department of Medicine

An Internist, Pulmonologist and Critical Care Medicine physician with great interest in diagnosis and management of pulmonary vascular disease, as well as innovations in critical care curricular designs and graduate medical education.

Pomann

Gina-Maria Pomann

Associate Professor of Biostatistics & Bioinformatics

Dr. Pomann is a biostatistician and educator with extensive research, leadership, and administrative experience. Her methodological contributions include the development of novel statistical methodology and predictive modeling techniques with applications to functional data and brain imaging. Collaborating with investigators across biomedical fields, Dr. Pomann has published in areas such as Surgery, Urology, and Hospital Medicine, among others. To support the development of efficient and effective data-intensive research across the biomedical sciences, Dr. Pomann’s primary research focuses on the science of team science. She works with collaborators with diverse scientific expertise to develop administrative structures, scientific operational processes, methods for organizing quantitative collaboration units, and workforce development programs.

Dr. Pomann currently serves as an Associate Professor of Biostatistics and Bioinformatics and is the Director of the Biostatistics, Epidemiology, and Research Design (BERD) Methods Core, a group of faculty and staff with diverse quantitative expertise (biostatisticians, data scientists, bioinformaticians, clinical informaticians, epidemiologists, etc.) contributing to groundbreaking research in clinical and translational domains. She has directed the development and management of 30 collaboration teams comprising biostatistics staff, faculty, and students. She has successfully developed collaboration teams across various medical fields, partnering with entities such as the Department of Pediatrics, the Global Health Institute, and the Department of Neurosurgery, to name a few. The programs she directs have helped over 1100 investigators identify appropriate collaborators with quantitative expertise and have led to the co-authorship of more than 550 collaborative manuscripts by quantitative staff and faculty within the BERD Core. More information about BERD can be found on our website: https://biostat.duke.edu/berd-methods-core .

In addition to building innovative processes and organizational structures to facilitate collaborations to drive data-intensive research, Dr. Pomann leads numerous workforce development programs for quantitative scientists. She develops processes and best practices to accelerate science and meet the evolving needs of data-driven clinical and translational research. Dr. Pomann developed the BERD Core Training and Internship Program (BCTIP), to provide a hands-on collaboration experience for Masters of Biostatistics students at Duke. She also oversees the Duke AI Health Fellowship Program, a two-year post graduate training program in data science and AI in Healthcare. Dr. Pomann is also MPI of an R25 titled "Quantitative Methods for HIV/AIDS Research" facilitating internships for quantitative students as well as a mentored scholars program and workshop series for biomedical investigators. Dr. Pomann holds a joint appointment at Duke National University of Singapore which allows her to develop training programs for the international workforce. The programs she directs have supported and trained more than 20 faculty, 40 staff, and 95 student interns to engage in data-intensive biomedical research.

Fortin

Terry Ann Fortin

Associate Professor of Medicine
Rajagopal

Sudarshan Rajagopal

Associate Professor of Medicine

I am a physician-scientist with a research focus on G protein-coupled receptor signaling in inflammation and vascular disease and a clinical focus on pulmonary vascular disease, as I serve as Co-Director of the Duke Pulmonary Vascular Disease Center. My research spans the spectrum from clinical research in pulmonary vascular disease, to translational research in cardiovascular disease, to the basic science of receptor signaling. 

Our basic science resesarch focuses on understanding and untapping the signaling potential of G protein-coupled receptors (GPCRs) to regulate inflammation in vascular disease. GPCRs are the most common transmembrane receptors in the human genome (over 800 members) and are some of the most successful targets for drug therapies. While it has been known for some time that these receptors signal through multiple downstream effectors (such as heterotrimeric G proteins and multifunctional beta arrestin adapter proteins), over the past decade it has been better appreciated that these receptors are capable of signaling with different efficacies to these effectors, a phenomenon referred to as “biased agonism”. Ligands can be biased, by activating different pathways from one another, and receptors can be biased, by signaling to a limited number of pathways that are normally available to them. Moreover, this phenomenon also appears to be common to other transmembrane and nuclear receptors. While a growing number of biased agonists acting at multiple receptors have been identified, there is still little known regarding the mechanisms underlying biased signaling and its physiologic impact.

Much of our research focuses on the chemokine system, which consists of approximately twenty receptors and fifty ligands that display considerable promiscuity with each other in the regulation of immune cell function in inflammatory diseases. Research from our group and others have shown that many of these ligands act as biased agonists when signaling through the same receptor. We use models of inflammation such as contact hypersensitivity and pulmonary arterial hypertension (PAH). PAH is a disease of the pulmonary arterioles that results in right heart failure and most of its treatments target signaling by GPCRs. We use multiple approaches to probe these signaling mechanisms, including in-house pharmacological assays, advanced phosphoproteomics and single cell RNA sequencing.


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