# Mechanisms of Arrhythmias Following Cardiac Irradiation

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $472,945

## Abstract

Radiation exposure during cancer treatment can cause significant cardiac morbidity and
mortality both acutely and years after the initial exposure. These short and long-term
complications are increasingly important as new therapies for cancer are developed and
survival improves. Radiation can directly damage the myocardium, cause coronary artery and
valvular disease, disrupt cardiac innervation and precipitate myocardial fibrosis; this can
subsequently lead to systolic and diastolic dysfunction along with atrial and ventricular
arrhythmias. In addition, radiation therapy is often given concomitantly with chemotherapy and it
is difficult to sort out the direct effects of radiation. The detailed mechanisms underlying the
susceptibility to tachy- and bradyarrhythmias following radiation therapy have not been defined.
We now show that short and long-term total body and cardiac targeted irradiation in mice leads
to oxidative stress, conduction system disease, serum miR-34a upregulation, arrhythmias and
increased mortality which were prevented, in part, by treatment with the water soluble oxetanyl
sulfoxide compound MMS350 that was developed as a radiation mitigator at the University of
Pittsburgh. We also show that Nitric Oxide Synthase 1 knockout (Nos1-/-) mice develop more
severe conduction disease associated with increased mortality, that Nos1 genotype alters the
effects of radiation on mitochondrial function and reactive oxygen species (ROS) metabolic
pathways, that Nos1 genotype alters the metabolic response to MMS350 following irradiation.
Our primary hypothesis is that NOS1 and microRNAs play heretofore unrecognized roles in
radiation-induced damage to the heart and cardiac conduction system by mitigating changes in
oxidative stress and mitochondrial dysfunction that lead to electrophysiological remodeling and
arrhythmias, and that MMS350 can mitigate the arrhythmogenic phenotype by protecting
cellular metabolism and energetics. To test these hypotheses, we will use total body and
cardiac targeted irradiation of wild type and genetically engineered mice to determine the
mechanisms by which conduction disease and arrhythmias result from damage to cardiac
myocytes, vascular smooth muscle and endothelial cells and/or the autonomic nervous system,
and to determine the mechanisms by which NOS1, MMS350 and microRNAs alter the damage.
These studies will define the role of Nos1 and microRNAs in cardiac conduction and
arrhythmias following radiation exposure and test pharmacological therapies that may mitigate
this potentially lethal side effect of a life-saving cancer therapies.

## Key facts

- **NIH application ID:** 10132391
- **Project number:** 5R01HL152104-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Barry London
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $472,945
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132391

## Citation

> US National Institutes of Health, RePORTER application 10132391, Mechanisms of Arrhythmias Following Cardiac Irradiation (5R01HL152104-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132391. Licensed CC0.

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