# Targeting Mitochondria in Single Ventricle Heart Disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $723,914

## 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, anectdotal 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:** 10156031
- **Project number:** 1R01HL156670-01
- **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:** $723,914
- **Award type:** 1
- **Project period:** 2021-03-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156031

## Citation

> US National Institutes of Health, RePORTER application 10156031, Targeting Mitochondria in Single Ventricle Heart Disease (1R01HL156670-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10156031. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*