# Targeting Vascular Leak and Intercalated Disk Nanodomains to Prevent Atrial Fibrillation

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $440,648

## Abstract

ABSTRACT
 Inflammation and vascular leak are common findings across several pathologies associated
with arrhythmias. These include atrial fibrillation (AF), which affects up to 3% of the US population.
AF progressively worsens, and increases risk of stroke and cardiovascular disease. Thus, we
urgently need novel, mechanistically-driven therapies for AF. Vascular leak in AF patients results
from elevated serum levels of inflammatory cytokines such as vascular endothelial growth factor
(VEGF). While the thrombogenic impact of vascular leak in AF is widely recognized, its role in
arrhythmogenesis remains unclear. One possible link between vascular leak and arrhythmia may
be myocardial edema. Recent work by the PI demonstrated that edema disrupts sodium channel
(NaV1.5) –rich nanodomains within the intercalated disk (ID), slowing cardiac impulse
propagation, and prompting arrhythmias. In preliminary studies, VEGF (at levels found in the
serum of AF patients) elevated AF inducibility ex vivo and in vivo mouse experiments within 30
minutes. Therefore, we hypothesize that cytokine-induced vascular leak promotes cardiac
edema, and contributes to atrial arrhythmias by disrupting NaV1.5-rich ID nanodomains. In
this venture, we will employ cutting edge tools including super-resolution microscopy, 3D electron
microscopy, and smart patch clamp to investigate the structural and functional impact of vascular
leak on the structure and function of atrial IDs. Furthermore, we will utilize an innovative strategy
peptide mimetics of adhesion domains will be used to selectively modulate the structure of
different ID nanodomains. Aim 1 will use these peptides to investigate how different ID
nanodomains contribute to atrial conduction, and probe fundamental mechanisms underlying
these structure-function relationships. In new preliminary data, we demonstrate that VEGF-
induced vascular leak induces swelling of ID nanodomains and translocation of NaV1.5 from these
sites within 30 minutes. Aim 2 will investigate the acute structural and functional impacts of VEGF-
induced vascular leak. Aim 3 will use ex vivo and in vivo models to test the efficacy of preserving
the vascular barrier and/or ID nanodomains in preventing AF.

## Key facts

- **NIH application ID:** 10171612
- **Project number:** 5R01HL148736-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Rengasayee Veeraraghavan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,648
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171612

## Citation

> US National Institutes of Health, RePORTER application 10171612, Targeting Vascular Leak and Intercalated Disk Nanodomains to Prevent Atrial Fibrillation (5R01HL148736-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10171612. Licensed CC0.

---

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