Introduction

Atrial fibrillation (AF) is the most common heart rhythm disorder, with an estimated prevalence of 12.1 million individuals in the US alone by 2030.1 AF is a cause of significant morbidity and mortality, and because the incidence of AF increases with age, it is fast becoming an epidemic worldwide.2,3 Despite its clinical importance, AF is a difficult condition to treat. Current therapies for AF include anti-arrhythmic drugs and ablation to electrically isolate the pulmonary veins.4 Ablation is mostly effective for paroxysmal AF, with more limited efficacy in persistent AF, and is also associated with complications. Anti-arrhythmic drugs have limited long-term efficacy and can be associated with significant adverse effects, including pro-arrhythmia and effects on the nervous system.5
Given these challenges, researchers are actively investigating new treatments, including gene-based approaches to directly and specifically target the signaling pathways in the atrial myocardium that underlie the creation of electrical and structural remodeling in AF. In the preclinical stage, promising results having been obtained in animal models that parallel the electrical and structural remodeling seen in humans. While gene therapy holds great hope to produce a highly effective and personalized treatment for a diverse range of cardiac disorders, safe and successful clinical translation is in a nascent phase and therapies must be designed with careful attention to an ever-expanding body of knowledge.
In this review, we will begin by discussing the current state and advances in gene transfer and gene-editing technology, with a focus on the gene therapy vectors and methods for delivery of these vectors to the atrium. We will then examine molecular targets based upon AF mechanisms. Further, we will discuss the potential of novel AF mapping strategies to better target gene therapy delivery.