Apelin increases atrial conduction velocity, refractoriness, and prevents inducibility of atrial fibrillation.

Young M Kim,Subodh Verma,Robert Lakin,Marco Perez,Maneesh Singh,Peter H Backx,Euan A Ashley,Jeffrey Olgin,Emily Wilson,Hao Zhang,Ayaaz Sachedina,Thomas Quertermous,Jack Liu

doi:10.1172/jci.insight.126525

Abstract

Previous studies have shown an association between elevated atrial NADPH-dependent oxidative stress and decreased plasma apelin in patients with atrial fibrillation (AF), though the basis for this relationship is unclear. In the current study, RT-PCR and immunofluorescence studies of human right atrial appendages (RAAs) showed expression of the apelin receptor, APJ, and reduced apelin content in the atria, but not in plasma, of patients with AF versus normal sinus rhythm. Disruption of the apelin gene in mice increased (2.4-fold) NADPH-stimulated superoxide levels and slowed atrial conduction velocities in optical mapping of a Langendorff-perfused isolated heart model, suggesting that apelin levels may influence AF vulnerability. Indeed, in mice with increased AF vulnerability (induced by chronic intense exercise), apelin administration reduced the incidence and duration of induced atrial arrhythmias in association with prolonged atrial refractory periods. Moreover, apelin decreased AF induction in isolated atria from exercised mice while accelerating conduction velocity and increasing action potential durations. At the cellular level, these changes were associated with increased atrial cardiomyocyte sodium currents. These findings support the conclusion that reduced atrial apelin is maladaptive in fibrillating human atrial myocardium and that increasing apelin bioavailability may be a worthwhile therapeutic strategy for treating and preventing AF.

Highlights

Atrial fibrillation (AF) is the most common clinical arrhythmia and is the leading cause of disabling stroke [1]
Given that plasma apelin levels have been shown to be decreased in patients with lone [25] and persistent AF [27], we began by measuring plasma apelin levels in patients
To assess the potential relevance of reduced atrial apelin levels, we looked for evidence of apelin receptor (i.e., APJ receptor) expression in the right atrial myocardium of patients undergoing cardiac surgery

Summary

Introduction

Atrial fibrillation (AF) is the most common clinical arrhythmia and is the leading cause of disabling stroke [1]. Electrophysiological remodeling in AF includes shortened atrial refractoriness and slowed conduction, which may be related to elevated atrial oxidative stress [5,6,7], and strategies to increase conduction velocity (CV) and/or increase refractoriness may protect against AF initiation, maintenance, and recurrence [8,9,10]. APJ receptors have been shown to directly regulate ventricular excitability, conduction, contractility, and refractoriness [22, 23] in association with increased cardiac peak sodium current and slowed recovery from inactivation [23]. Apelin immunoreactivity is 200-fold greater in atrial versus ventricular tissue [23, 24], suggesting a role in the regulation of atrial electrophysiology.

Methods

Results

Conclusion