# Clinical, Genetic, and Proteomic Risk Factors for Pulmonary Hypertension in Heart Failure

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $787,763

## Abstract

PROJECT SUMMARY
At least 50% of people with HF develop pulmonary hypertension (HF-PH). The fact that all people with HF
have elevated left ventricular filling pressures suggests that there must be additional factors that drive the
development of PH. Identifying these factors is important because HF-PH carries a 50% increase in mortality
and no treatments exist to improve outcomes or prevent PH development. Epidemiologic data on the risk
factors and natural history of HF-PH are lacking. Similarly, the biological mechanisms underlying HF-PH are
unknown because no molecular studies have been performed in this population. In addition to establishing
incidence rates and clinical risk factors, an important goal of this application is to identify molecular features
associated with HF-PH and right ventricular (RV) compensation (i.e. preserved RV function in the setting of
PH). We hypothesize that (1) HF-PH incidence rates using echocardiographic data are higher than previously
reported rates based on medical codes (2) HF-PH and RV compensation are genetically influenced, and (3)
protein biomarkers will be associated with prevalent HF-PH and RV function. These hypotheses are based on
our preliminary showing: 1) higher rates of incident HF-PH using echo data than rates based on medical codes
alone; 2) association of poor metabolic health with HF-PH and RV dysfunction; 3) high genetic heritability of
pulmonary pressure; 4) shared genetic risk between obesity and pulmonary pressure; 5) a genetic association
between insulin resistance and PH; and 6) elevation of inflammatory and vascular tone proteins in HF-PH
patients. Developing large, prospective cohorts designed to study the natural history of HF-PH would be
prohibitively expensive and inefficient. Leveraging electronic health record (EHR)-based cohorts linked to
biobanks presents a scientifically valid, cost-effective, and efficient pathway for studying HF-PH epidemiology
and pathophysiology. In Aim 1, we will establish HF-PH incidence rates and examine the importance of
modifiable risk factors for HF-PH (e.g. obesity, insulin resistance) by extracting echocardiographic PASP
values on ~425,000 individuals in the Veterans Affairs and Vanderbilt EHRs (64,000 African Americans and
85,000 women). Approximately 100,000 of these individuals have repeat PASP measurements, and 65,000
have gold standard RHC data. Both cohorts are well phenotyped with detailed data on demographics,
comorbidities, medication exposure, laboratory, and clinical events. In Aim 2, we will leverage the VA-funded
Million Veterans Program and Vanderbilt's BioVU to analyze genome-wide genotyping data in a total of 25,000
subjects with HF at no cost to this application. In Aim 3, we will perform proteomic profiling (1129 proteins) in
discovery (800 subjects) and replication (600 subjects) HF cohorts collected through BioVU. We have
combined existing resources with new phenotypic, genotypic, and proteomic data and assembled a team with
the s...

## Key facts

- **NIH application ID:** 10163899
- **Project number:** 5R01HL146588-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Evan L Brittain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $787,763
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163899

## Citation

> US National Institutes of Health, RePORTER application 10163899, Clinical, Genetic, and Proteomic Risk Factors for Pulmonary Hypertension in Heart Failure (5R01HL146588-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10163899. Licensed CC0.

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