# Lipid Peroxidation-Induced Mitochondrial Injury Inhibits Vascular Function in Single Ventricle Congenital Heart Disease > **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $653,424 ## Abstract PROJECT SUMMARY/ABSTRACT Over 50% of long-term survivors of the Fontan operation with single ventricle congenital heart disease develop heart failure, for which standard therapies (ACE inhibitors, β-blockers) are largely ineffective. Thus, a major challenge in treating Fontan heart/circulation failure is in understanding its unique mechanisms that differentiate it from the more common acute ischemia-related heart failure and identifying new therapeutic targets. The overarching goal of this proposal is to develop new therapeutic targets to preserve heart function, and to identify biomarkers to detect heart/circulation failure earlier in the clinical course of patients with a Fontan circulation. We have previously identified chronic oxidative stress-induced mitochondrial injury as a major mechanism in Fontan failure. We hypothesize that oxidative stress induces cardiomyocytes to release damaged mitochondria that impair endothelial function in both the heart (local) and peripheral vasculature (plasma) in patients with Fontan failure. We examine this general question through the lens of cell-cell communication in the cardiovascular system. In Aim 1, we will evaluate the role of chronic non-ischemic oxidative stress in causing mitochondrial dysfunction in Fontan failure. We will use myocardial tissue to assess lipid peroxidation-induced mitochondrial dysfunction, correlate mitochondrial dysfunction with severity of clinical illness and how damaged mitochondria can be packaged and transported in extracellular vesicles to mediate cell-cell communication. In Aim 2, we will investigate whether lipid peroxidation-induced mitochondrial injury impairs cardiac vascular function. We will show that cardiac vascular dysfunction is a critical component of Fontan failure which may serve as a novel therapeutic target. We will assess endothelial mitochondrial dynamics in myocardial tissue from children with Fontan failure, assess cardiomyocyte and endothelial cell-cell communication via extracellular vesicles and phenotype the cardiac microvascular tree to assess for lipid peroxidation and cell death. In Aim 3, we will determine circulating biomarkers to monitor clinical status in children with and without Fontan failure and compare to control. We will show that circulating extracellular vesicles carrying oxidatively damaged mitochondria cause peripheral vascular endothelial dysfunction, determining the role of extracellular vesicles in initiating metabolic reprogramming, both locally and in distant organs. Using innovative approaches, including 3D human tissue imaging and high throughput quantitative proteomics, in a large cohort of patients with a Fontan circulation, we will test our hypothesis and examine the effectiveness of new mitochondrial-targeted therapies, including repurposing the FDA-approved small molecule elamipretide to target lipid peroxidation. Through better understanding of the unique mechanisms of Fontan failure, our team of clinicians and expert... ## Key facts - **NIH application ID:** 10868746 - **Project number:** 5R01HL165245-02 - **Recipient organization:** STANFORD UNIVERSITY - **Principal Investigator:** Sushma Reddy - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $653,424 - **Award type:** 5 - **Project period:** 2023-07-01 → 2027-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10868746 ## Citation > US National Institutes of Health, RePORTER application 10868746, Lipid Peroxidation-Induced Mitochondrial Injury Inhibits Vascular Function in Single Ventricle Congenital Heart Disease (5R01HL165245-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10868746. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*