Pulmonary hypertension (PH) is a non-specific term to describe elevation in pulmonary artery (PA) pressure. Broadly, PH may be caused by elevations in left atrial pressure, increased flow through the PA and true pulmonary vascular pathology. Yet one of the most vexing problems in the ontology of PH is the presence of pressures that seem excessively high in patients with known lung and heart diseases. The current descriptors of these patients include "out of proportion" PH and "combined" disease from the World Symposium on PH in 2013. Our application focuses on patients with C-PH in the context of elevated left atrial pressure with PH that is greater than would be expected by purely passive mechanisms. Because C-PH is so poorly defined, almost nothing is known about this phenotype. C-PH is commonly found in patients with diastolic and systolic left heart dysfunction and has been associated with worse prognosis in these conditions, but we presently lack any specific therapy for C-PH. Our group has published on the differentiation of pulmonary arterial hypertension (due to pulmonary arterial remodeling, PAH) from Group II PH (passive pulmonary hypertension due to left atrial hypertension) and has studied patients with PH out of proportion to left atrial hypertension. Further we have identified metabolic syndrome associations with PH in animal models and affected patients. We have developed an infrastructure for PH patient clinical and research phenotyping including a large biobank that we have used to identify genetic variants associated with heritable pulmonary vascular disease collaboratively with other groups. We now hypothesize that genetic variants and metabolic traits contribute to development of C-PH associated with left atrial hypertension and can be exploited to define endophenotypes and dynamically identify subsets of PH patients that are likely to respond to targeted therapeutics. Our proposal includes three specific aims to test this hypothesis. First we will physiologically and clinically phenotype C-PH to demonstrate the presence of fixed pulmonary vascular disease unlike Group II PH. Second we will use forward and reverse phenotyping with whole exome sequencing, transcriptomic and metabolomic data to define a molecular classification of PAH, Group II PH and C-PH. We will confirm our findings using BioVu, a Vanderbilt DNA databank with deidentified patient information. Third, we will dynamically phenotype C-PH patients to identify those likely to respond to PAH-directed therapy. At the conclusion of these studies we will have identified common genetic and metabolic features of C-PH and used dynamic phenotyping to recognize C-PH patients likely to respond to PAH-directed therapy. These studies will form a construct for building a molecular classification of all PH and proof of concept that certain molecularly- defined phenotypes can be identified prior to treatment and guide optimal therapy.

Public Health Relevance

Although pulmonary hypertension has been classified by underlying pathology and physiology, our current schema fails to classify approximately 1/5 patients with pulmonary hypertension. In particular, patients with mild elevations in pulmonary wedge pressure and pulmonary hypertension that is out of proportion, so called combined pulmonary hypertension, are common and thus far unstudied. This application proposes a phenotyping protocol for pulmonary hypertension and aims to show that combined pulmonary hypertension is characterized by intrinsic pulmonary vascular disease and genetic variants with transcriptomic and metabolomic signatures similar to pulmonary arterial hypertension that can be leveraged to identify a priori treatment responses with the long-term goal to develop a molecular classification of pulmonary hypertension that facilitates better mechanistic understanding of disease and optimal therapy recommendations

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL125212-01
Application #
8796005
Study Section
Special Emphasis Panel (ZHL1-CSR-P (S1))
Program Officer
Xiao, Lei
Project Start
2014-09-17
Project End
2019-07-31
Budget Start
2014-09-17
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$235,502
Indirect Cost
$85,501
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212