# Metabolic Function in Pulmonary Vascular Disease

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $644,419

## Abstract

SUMMARY
Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular obliteration, right
heart failure and death. Despite several approved therapies, none are curative or address the primary
molecular drivers of this highly morbid disease. Work by our group and others has highlighted the role of
metabolic dysregulation such as mitochondrial dysfunction, insulin resistance and cardiac lipotoxicity in PAH.
During the first term of our program project grant, we have published that glucose intolerance is common in
human PAH and impacts survival. We have also assessed the effects of insulin-mediated mitochondrial lipid
metabolism on the right ventricle (RV) and demonstrated that lipid deposition may be a key feature of RV
dysfunction in PAH. Important questions remain: do interventions against insulin resistance improve PAH? Are
there specific patients most likely to benefit from interventions against insulin resistance? Drug therapy, e.g.
metformin, and exercise are the major currently practical interventions against insulin resistance in PAH. We
initiated a pilot study of metformin in PAH patients in the first period of this grant with endpoints of safety, effect
on plasma markers of oxidant stress and RV lipid deposition. We have enrolled nearly half of our target with no
safety concerns. In preliminary analyses we have found that metformin in PAH may reduce RV lipid content
and change plasma amino acid levels indicative of increased nitric oxide production. We and others have
published that PAH patients are highly sedentary with reduced skeletal muscle function, suggesting that
activity may be a modifiable feature of PAH. Exercise is known to be safe in PAH, but implementation in the
US is limited by access to care. Our group recently showed that linking activity monitoring, e.g. fitbit, with
automated, personalized text prompts to encourage activity led to a 300% increase in step counts. This
approach may provide an innovative, inexpensive mechanism to increase activity in PAH, and thereby reduce
insulin resistance. The mechanisms by which these insulin-sensitizing interventions may improve 6MWD and
outcomes in PAH is unknown, however. Our preliminary data suggests metformin may reduce RV lipid content,
which may affect the primary cause of death in PAH, RV failure. We now propose to test the hypothesis that
interventions to improve insulin resistance will improve exercise capacity and functional class in PAH. We
propose three specific aims to test this 1) A prospective 2x2 factorial design 12-week clinical trial of metformin
or placebo and activity intervention or usual care to assess effect on six minute walk and functional class, 2)
Assessment of the interventions in Aim 1 on RV and peripheral muscle function and lipid content and markers
of pulmonary vascular disease to define how these interventions may work in PAH and 3) Identify and
prospectively test peripheral blood markers of metformin response in PAH. The br...

## Key facts

- **NIH application ID:** 9987696
- **Project number:** 5P01HL108800-10
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** JOHN Hughes NEWMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $644,419
- **Award type:** 5
- **Project period:** 2012-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987696

## Citation

> US National Institutes of Health, RePORTER application 9987696, Metabolic Function in Pulmonary Vascular Disease (5P01HL108800-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9987696. Licensed CC0.

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