Pathophysiological Significance of Atrial Fibrillation Electrogram Patterns

心房颤动（AF）是最常见的心律失常，是中风的主要原因。尽管它

Atrial fibrillation (AF) is the most common heart rhythm disorder and is a major cause of stroke. Despite its rapidly rising incidence, current therapies are suboptimal. This is largely because current AF therapies, including ablation, are not targeted to the fundamental mechanisms underlying AF. AF is characterized by complex electrical activation patterns that are difficult to map using standard activation time mapping. Yet, there is growing evidence that AF is driven by stable sources in the atria, such as rotors or focal activity. Unfortunately, previous attempts to use AF electrograms to detect these sources have had mixed success. We have recently developed an electrogram morphology recurrence (EMR) analysis that appears to more accurately reflect molecular and electrophysiological substrate for AF than previously described AF electrogram measures of AF. Our recent studies suggest that regions of high recurrence morphology with the shortest cycle lengths (i.e. regions of low recurrence cycle length - CLR) may correspond to regions of increased parasympathetic innervation and/or increased oxidative injury. Furthermore, our clinical studies suggest that in patients with persistent AF, EMR mapping is both feasible and provides important physiologic information. Our overall hypothesis for this proposal is: ‘sites of high recurrence morphology with the shortest cycle length (i.e. CLR) represent regions of increased autonomic signaling and/or increased oxidative injury, which are critical to the maintenance of persistent AF.’ To test this hypothesis, we will use novel gene therapy approaches developed in our lab, as well as a CLR-guided ablation strategy in patients with persistent AF. In Specific Aim 1, we will assess in a canine rapid atrial pacing model of AF whether targeted inhibition of parasympathetic signaling – by expression of plasmids expressing Gαi/o inhibitory peptides (Gαi/o_ct) at the atrial sub-region with lowest CLR – will reverse electrical remodeling and AF. In Specific Aim 2, we will assess in the same canine model whether targeted inhibition one or more of the two major sources of oxidative injury in AF - by expression of NOX2 shRNA  mitochondrial catalase at the atrial sub-region with lowest CLR – will reverse electrical remodeling, prevent progression of fibrosis and decrease AF. In Specific Aim 3, patients with persistent AF who are undergoing catheter ablation will be randomized to a CLR guided ablation strategy or PVI alone; we will determine whether in these patients a CLR guided ablation strategy will increase ECG dominant frequency compared to PVI alone. Completion of all the aims will provide a clear path to using EMR mapping as a new diagnostic method to guide therapeutic intervention for AF. This proposal leverages the prior development and validation of EMR to test several novel targeted approaches for treating AF. As AF may have complex underlying pathophysiology, it is feasible that one or more of these approaches could be therapeutic and could ultimately be used in combination. This proposal provides a critical platform to advance the science of curative therapy for AF.