# The Association of Metabolic Disease and Pulmonary Hypertension

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $570,691

## Abstract

Project Summary/Abstract
Obesity is a pressing medical need: it affects one-third of adults in the US, and more than 80% of people with
diabetes mellitus are overweight or obese. In animal models, multiple obesity-related pathways lead to
pulmonary hypertension (PH), including insulin resistance, inflammation, oxidative stress, and adipokine
signaling. Few studies have examined the association of metabolic dysfunction and PH in humans. We
postulate that obesity-related metabolic disease leads to pulmonary vascular dysfunction, and may represent
an early phenotype in the transition to heart failure. It is recognized that metabolic disease leads to endothelial
dysfunction; when localized to the pulmonary circulation, pulmonary endothelial dysfunction is an integral driver
of the pathobiology of PH. We hypothesize that metabolic disease may lead to pulmonary artery endothelial
cell (PAEC) dysfunction as a driver of PH. We propose to study 250 obese non-diabetic individuals with
exertional dyspnea. To gain further insights into underlying mechanisms of obesity-related PH, we will pursue
three related lines of investigation: In Aim 1, we will investigate the association of metabolic disease and
pulmonary artery endothelial cell (PAEC) phenotype with pulmonary hemodynamics in human subjects. Using
a novel technique to isolate fresh human PAECs at the time of right heart catheterization, we will profile PAEC
phenotypes including endothelial insulin signaling (insulin-mediated endothelial nitric oxide synthase
phosphorylation) and adenosine monophosphate-activated protein kinase activation. In Aim 2, we will study the
dynamic pulmonary vascular responses to cardiopulmonary exercise testing in metabolic disease. Pulmonary
vascular function will be precisely characterized at rest and during cycle ergometry exercise testing with
simultaneous hemodynamic monitoring in order to evaluate multi-point pulmonary artery pressure-cardiac
output relationships and pre- and post-capillary components of PH. In Aim 3, we will conduct a randomized
intervention study, to examine the effect of metformin versus placebo on pulmonary vascular function and
PAEC phenotype in obese individuals. This proposal leverages a unique multidisciplinary team of collaborators
with expertise in cardiovascular and metabolic disease, endothelial biology, PH, exercise physiology,
endocrinology, and biostatistics. These studies have the potential to provide important insights into
mechanisms driving PH in metabolic disease, and will lay the foundation for future studies focused on disease
prevention and optimal therapies in obesity-related cardiovascular disease.

## Key facts

- **NIH application ID:** 9955289
- **Project number:** 5R01HL134893-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jennifer E Ho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $570,691
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955289

## Citation

> US National Institutes of Health, RePORTER application 9955289, The Association of Metabolic Disease and Pulmonary Hypertension (5R01HL134893-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9955289. Licensed CC0.

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