# Targeting mitochondria in SV heart disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $76,211

## Abstract

Project Summary
With advancements in operative techniques and perioperative management, there is an
increasing number of patients with single ventricle congenital heart disease (SV) that are
surviving into childhood and beyond. Due to the chronic pressure and volume load placed on
the single systemic ventricle, these patients remain at constant risk for the development and
progression of cardiac failure. Unfortunately, very little is known about how the failing SV heart
differs from the failing pediatric or adult biventricular heart. Additionally, the transition to heart
failure that occurs in the SV heart is also incompletely understood. This lack of understanding in
the mechanisms underlying SV heart failure are a major hurdle in the identification of effective
targeted therapies. In addition, the rarity of SV makes it very difficult to perform prospective
controlled drug studies as is routinely done in the adult heart failure population and as a result,
treatments are based on extrapolation of clinical trials from different patient populations,
anecdotal experience, or potential for theoretic perceived benefit. Phosphodiesterase-5
inhibitors (PDE5i), such as sildenafil, are an example of such a therapy that is increasingly used
in the SV patient population with a limited existing evidence-basis. Widespread, and fairly
indiscriminate use of PDE5i for SV patients is driven in part by several publications suggesting
positive clinical results in small series of SV patients. The recently published NHLBI FUEL
(Fontan Udenafil Exercise Longitudinal assessment) trial demonstrated improved submaximal
exercise in 400 fontan patients. These encouraging studies combined with our recent
publication demonstrating increased PDE5 expression and activity in failing SV hearts
suggesting that the myocardium may be a viable target of PDE5i.
While historically the rationale for the use of PDE5i in SV is to augment pulmonary blood flow,
we hypothesize that the failing SV myocardium, and specifically the mitochondria, represent a
target of PDE5i therapy as well. Our preliminary data demonstrate: (1) Mitochondrial
dysfunction, altered sirtuin signaling, and increased mitochondrial protein acetylation in failing
SV myocardium (SVHF); (2) Decreased mitochondrial reactive oxygen species (ROS)
generation detected by Electron Paramagnetic Resonance (EPR) in failing SV hearts treated ex
vivo with PDE5i; (3) Decreased protein acetylation and improvement in mitochondrial function in
failing SV hearts treated ex vivo with PDE5i; (4) Impaired mitochondria function in SV Non-
Failing (SVNF) (primary transplant or Norwood specimens) hearts treated ex vivo with PDE5i;
and (5) Mitochondrial dysfunction and increased ROS in primary cardiomyocytes treated with
SVHF patient serum, which is improved by the addition of PDE5i or the SIRT 3 activator,
honokiol (HNK). We hypothesize that mitochondrial dysfunction is involved in the HF transition
of SV hearts, and that PDE5i improves mitoc...

## Key facts

- **NIH application ID:** 10414711
- **Project number:** 3R01HL156670-01S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Shelley Deanne Miyamoto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,211
- **Award type:** 3
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414711

## Citation

> US National Institutes of Health, RePORTER application 10414711, Targeting mitochondria in SV heart disease (3R01HL156670-01S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10414711. Licensed CC0.

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