# Exploring the Molecular Physiology of Atrial Fibrillation

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $718,065

## Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and
mortality. Despite decades of research current treatments remain only partially effective, or in the case of
ablation, invasive, costly and not effective in some patients. Development of novel, effective and safe therapy
for AF has been hampered by the lack of animal models that reflect AF in humans. While some large animal
models exhibit aspects of human AF it is difficult to test and develop novel small molecule therapies for AF in
these costly and limited models. Ideally, a small animal model that faithfully phenocopies human AF would be
an invaluable tool for both understanding the molecular physiology of AF and potentially for identifying and
testing novel small molecule therapeutics. Indeed, murine models have proved invaluable in the development
of novel therapeutics for cancer, diabetes and obesity. The lack of a mouse model for AF is a barrier to
research in this important disease. To address this gap we created doxycycline-inducible transgenic (TG) mice
with a mutation (F1759A) of the local anesthetic binding site in human SCN5A, the cardiac NaV1.5 channel
gene. Fortuitously these mice exhibit modest atrial enlargement and fibrosis, mitochondrial dysmorphology,
frequent, sustained episodes of spontaneous AF, and non-sustained polymorphic ventricular tachycardia,
observed as early as 5 weeks of age in the absence of doxycycline. The sustained and spontaneous atrial
arrhythmias, an unusual if not unique phenotype in mice, enabled initial explorations of mechanisms of AF
using in vivo (telemetry), ex vivo (optical voltage mapping), and in vitro (cellular electrophysiology) techniques.
We now propose to use this mouse model to more fully characterize the molecular mechanisms of
arrhythmogenesis, to explore whether altered Ca2+ homeostasis contributes to the genesis and maintenance of
AF, and whether targeting altered Ca2+ homeostasis could be an effective treatment of AF. Three Aims are
proposed: Aim 1: To examine the downstream mechanisms by which increased cytosolic Ca2+ increases the
propensity of AF. We will test using genetic and pharmacological approaches whether inhibitors of Na+-Ca2+
exchanger (NCX) and Ca2+-calmodulin dependent kinase (CaMKII) can inhibit AF in vivo and and spiral
waves/rotors ex vivo. Aim 2: To test the causal link between increased persistent Na+ current, “leaky” RyR2,
and the susceptibility for AF. We will use pharmacological and genetic approaches to inhibit RyR2 leak to see
whether it plays a role in AF and whether it may be a novel therapeutic target. Aim 3: To test the causal link
between mitochondrial dysfunction due to increased persistent Na+ current and leaky RyR2 channels, and the
susceptibility for AF. The proposed studies may identify important links between dysfunctional Na+ channels,
abnormal SR Ca2+ release in AF, defective Ca2+-dependent signaling in AF, mitochondrial dysfunction and
oxidative...

## Key facts

- **NIH application ID:** 9838796
- **Project number:** 5R01HL140934-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ANDREW Robert MARKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $718,065
- **Award type:** 5
- **Project period:** 2018-01-17 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838796

## Citation

> US National Institutes of Health, RePORTER application 9838796, Exploring the Molecular Physiology of Atrial Fibrillation (5R01HL140934-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838796. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*