# Targeting Metabo-Redox Network Vulnerability in Heart Failure and Sudden Death

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $536,075

## Abstract

Heart failure (HF) is increasing in prevalence and incidence in the US. Despite advances in treatment, mortality is
~50% within 5 years of diagnosis with half of those deaths from sudden cardiac death (SCD), many before ejection
fraction has decreased to a qualifying level for an implantable defibrillator (EF35%). There are no effective therapies
to specifically treat SCD, apart from a defibrillator, which is palliative, not preventive. The multifactorial nature of
HF/SCD requires an approach that considers the integrative physiology of both the myocyte and the organ, and a
suitable experimental model with features of the human disease. This project leverages a unique guinea pig HF model
that recapitulates many important aspects described in human heart failure, including long QT syndrome,
arrhythmogenic SCD, inflammation, extracellular matrix remodeling, impaired Ca2+ handling, metabolic remodeling,
and oxidative stress. Employing cellular experiments with a multi-omic approach, our recent and new data provides
a comprehensive understanding of the genes, proteins, and fluxes (ionic and metabolic) behind the pathophysiology
of HF/SCD. We identified important control points involved in acute emergent events, such as impaired metabo-redox
coupling leading to mitochondrial ROS (mROS) overload and SCD, and those that mediate chronic remodeling,
characterized by suppression of metabolic and redox transcriptional programs, lowering the threshold for the acute
events.
 Our exciting preliminary data shows that both SCD and HF can be prevented or reversed by treatment with the
mitochondrial ROS (mROS) scavenger, mitoTEMPO. For the first time, we show that mROS drives chronic
remodeling of the specific phosphoproteome and the expression proteome in HF, likely through mitogen-activated
protein (MAP) kinase activation. Remarkably, the design of our mROS scavenger protocol allows us to discriminate
between mechanisms impacting SCD risk versus those that alter contractile function. Thus, the overarching goal of
this application is to determine which proteins are targets of acute regulation by mROS, contributing to
SCD/arrhythmia risk, versus those that are implicated in chronic HF remodeling. We hypothesize that mROS acutely
impairs Ca2+ handling and repolarization, but also acts as a second messenger causing negative HF outcomes by
disrupting the normal coupling between cytosolic signals and the nuclear gene programs driving mitochondrial
function, antioxidant enzymes, Ca2+ handling and action potential repolarization and that the chronic effects of mROS
are transduced through activation of MAP kinases. Our aims are to 1) determine protein/phosphoprotein targets
regulated by mROS that discriminate between high arrhythmia/SCD risk and the HF state, 2) determine the
acute versus chronic contribution of mROS to the electrophysiologic, EC-coupling and ROS abnormalities
underlying SCD and HF in myocytes and intact animals, and 3) determine which branch of the MAP ...

## Key facts

- **NIH application ID:** 9873990
- **Project number:** 5R01HL134821-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** D Brian Foster
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,075
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873990

## Citation

> US National Institutes of Health, RePORTER application 9873990, Targeting Metabo-Redox Network Vulnerability in Heart Failure and Sudden Death (5R01HL134821-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873990. Licensed CC0.

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