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.