A Chemogenetic Approach for the Treatment of Atrial Fibrillation

Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia and is responsible for significant morbidity, mortality, and burden on the health care systems. Importantly, AF events may promote further fibrillatory episodes by inducing atrial remodelling.

Limitations of Traditional Therapies

Traditional therapies for AF have relatively limited efficacy and are either:

• Destructive (ablation)
• Painful (defibrillation)
• Associated with side effects due to their global cardiac and systemic actions (drugs)

Consequently, novel treatment modalities for AF are direly needed.

Proposed Treatment

Here, we propose to develop a targeted, functional, non-destructive, and easily administered treatment for AF termination that does not cause pain or other side effects, which can also potentially prevent the associated atrial remodelling.

Chemogenetics Approach

Our proposed treatment is based on chemogenetics. This approach, which transformed neuroscience, utilizes inert drugs or designer molecules that have no effect on native host cells but can modulate the electrical properties of cells that are genetically modified to express specific chemogenetic receptors.

Recently, we showed the feasibility of using chemogenetic tools for modulation of cardiac excitability. Here, we aim to evaluate the potential anti-arrhythmic capabilities of our newly created chemogenetic construct, which can cause transient electrical silencing in response to an inert drug.

Potential Impact

This approach has the potential to be the first chemogenetic tool capable of “defibrillating” cardiac tissue in a highly targeted manner. To evaluate the potential of this concept for treating AF, we plan to:

1. Optimize its use
2. Study its effects in an in vitro human cardiac tissue model of reentrant arrhythmias
3. Investigate its effects in an in vivo AF rodent model

The suggested approach represents a paradigm shift in the way AF can be treated and opens a pathway to targeting additional cardiac arrhythmias.