# New and Disruptive Therapeutic Approaches to Target Fundamental Molecular Mechanisms Underlying Atrial Fibrillation

> **NIH NIH R35** · NORTHWESTERN UNIVERSITY · 2022 · $960,000

## Abstract

PROJECT SUMMARY
Atrial fibrillation (AF) is the most common heart rhythm disorder that affects >3 million Americans and is a
major cause of stroke. Since AF is primarily an age-related disease, it is fast becoming an epidemic in a rapidly
aging population. Unfortunately, current therapeutic approaches to AF – both pharmacological and ablation-
based - are sub-optimal in patients with persistent AF. This is thought to be because current treatments do not
target the fundamental, molecular mechanisms that cause AF. Over the last several years, the Arora lab at
Northwestern University has worked hard to better understand the molecular mechanisms underlying AF, with
the long term goal of developing a mechanism-guided therapeutic approach to AF. Work done in the Arora lab
over the last several years in large animal models of AF has demonstrated that autonomic nervous system
signaling, oxidative injury and CAMKII signaling are important mechanisms leading to electrical remodeling of
key ion channels and excitation contraction coupling proteins in the atrium, thereby leading to the
establishment of substrate for paroxysmal AF. The goal of the Arora lab over the next several years is to obtain
a better understanding of the molecular mechanisms that underlie the progression of paroxysmal AF to
persistent AF. We postulate that structural changes in the atrium such as new parasympathetic nerve
sprouting, NLRP3 inflammasome mediated fibrosis and HDAC6 mediated breakdown of microtubules (derailed
proteastasis) are key mechanisms underlying this progression of AF. We will study these mechanisms in
chronically tachypaced large animal models of AF by using novel gene therapy approaches developed in our
lab over the last several years. Success of these gene therapy approaches in arresting progression of
paroxysmal AF to persistent AF will also demonstrate their therapeutic potential. Since our eventual goal is to
develop a clinically viable gene therapy approach for persistent AF, we have recently conceived of a highly
novel electroporation-based approach to facilitate trans-venous gene delivery. In addition to identifying novel
gene therapy targets for AF, another major goal of this R35 proposal will be to fully develop and optimize this
gene delivery approach.
The next phase of the research proposed in the Arora lab is not only expected to give fresh mechanistic
insights into the creation of an atrial myopathy that supports persistent AF, but is also expected to led to the
development of new, potentially paradigm-shifting therapeutic approaches to AF.

## Key facts

- **NIH application ID:** 10355010
- **Project number:** 1R35HL161249-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Rishi Arora
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $960,000
- **Award type:** 1
- **Project period:** 2022-01-20 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355010

## Citation

> US National Institutes of Health, RePORTER application 10355010, New and Disruptive Therapeutic Approaches to Target Fundamental Molecular Mechanisms Underlying Atrial Fibrillation (1R35HL161249-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10355010. Licensed CC0.

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