# Evaluating NAD Supplementation as a Novel Treatment for Arrhythmias

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $591,581

## Abstract

The inward depolarizing Na+ current (INa) through the cardiac Na+ channel Nav1.5, encoded by
SCN5A, plays a critical role in regulating the action potential of myocytes in the heart. Nav1.5 post-
translational modifications (PTMs) and binding proteins can alter channel abundance and/or
electrophysiological properties. Loss of function mutations in SCN5A cause inherited arrhythmia
syndromes including Brugada syndrome (BrS) and conduction system disease by changes in
transcription, translation, channel properties and membrane trafficking. Alterations in Nav1.5 can also
exacerbate arrhythmias in common acquired conditions such as heart failure.
 NAD+ and NADH are critical regulators of myocardial bioenergetics and redox state, and NAD+ is a
required substrate for sirtuins that regulate acetylation. Our laboratory reported that mutations in the
NAD+/NADH dependent enzyme Gylcerol-3 Phosphate Dehydrogenase-1 Like (GPD1-L) cause BrS by
altering Nav1.5 membrane trafficking. We and others then showed that NAD+ increases INa in cell lines
and cardiac myocytes, at least in part through changes in reactive oxygen species (ROS) and PKC-
mediated phosphorylation in the intracellular Nav1.5 Domain III-IV linker. We have engineered Gpd1l-
targeted mice that have decreased INa, conduction disease, arrhythmias and altered Nav1.5 PTMs.
 Nicotinamide Riboside (NR), a highly bioavailable NAD+ precursor, increases INa in heterologous
expression systems and myocytes, and shortens QRS duration in mice. The mechanism(s) by which
NAD+ supplementation alters Nav1.5 membrane trafficking and INa remains unclear. In addition, how
multiple PTMs alter Nav1.5 and INa in a coordinated manner has not been studied.
 The central hypothesis of this proposal is that cellular metabolism alters the NAD+ metabolome,
regulating Nav1.5 by coordinated interactions of PTMs and binding proteins that act at the Nav1.5
Domain III-IV linker. To test this hypothesis, we will 1) Determine how NAD+ precursors and inhibitors
modify the NAD+ metabolome, redox state, Nav1.5 PTMs, INa and arrhythmias using cardiac myocytes
and mouse models; 2) Determine whether NAD+ precursors act in a coordinated manner at the Nav1.5
Domain III-IV linker via SIRT1-mediated deacetylation, PKC-mediated phosphorylation and α-actinin 2
binding; and 3) Identify the Nav1.5 PTMs modulated by GPD1-L.
 The primary goal of this proposal is to identify the mechanisms by which NAD+ metabolism affects
Nav1.5 expression and function. Ultimately, we hope to determine whether increasing membrane
Nav1.5 with NAD+ precursors or other metabolic modulators can prevent arrhythmias in inherited Na+
channel deficiency syndromes and in more common conditions such as heart failure.

## Key facts

- **NIH application ID:** 10138007
- **Project number:** 5R01HL147545-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Charles M Brenner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $591,581
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138007

## Citation

> US National Institutes of Health, RePORTER application 10138007, Evaluating NAD Supplementation as a Novel Treatment for Arrhythmias (5R01HL147545-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10138007. Licensed CC0.

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