R01HL156670

Targeting Mitochondria in SV Heart Disease - 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 is 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. As a result, treatments are based on extrapolation of clinical trials from different patient populations, anecdotal experience, or potential for theoretical 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, suggest 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.
(5) Mitochondrial dysfunction and increased ROS in primary cardiomyocytes treated with SVHF patient serum, which is improved by the addition of PDE5I or the SIRT3 activator, honokiol (HNK).

We hypothesize that mitochondrial dysfunction is involved in the HF transition of SV hearts, and that PDE5I improves mitochondrial function in failing SV hearts in a sirtuin-dependent manner. We propose the use of human tissue and a cardiomyocyte model to complete the proposed experiments.

The purpose of this project is to understand the transition to HF in the SV population and provide pre-clinical evidence to inform more targeted use of PDE5I, with the goal of optimizing clinical care and improving outcomes.

The Regents Of The Univ. Of Colorado

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Colorado United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the End Date has been extended from 08/31/25 to 01/31/26 and the total obligations have increased 435% from $723,914 to $3,873,722.