Apelin increases atrial conduction velocity, refractoriness, and prevents inducibility of atrial fibrillation
Young M. Kim, … , Peter H. Backx, Euan A. Ashley
Young M. Kim, … , Peter H. Backx, Euan A. Ashley
Published September 3, 2020
Citation Information: JCI Insight. 2020;5(17):e126525. https://doi.org/10.1172/jci.insight.126525.
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Research Article Cardiology

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

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.

Authors

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

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Figure 1

Molecular characterization of human apelin receptor, APJ, in human right atrial appendage and relationship between atrial and plasma apelin content with atrial NADPH oxidase activity.

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Molecular characterization of human apelin receptor, APJ, in human right...
(A) Plasma PYRapelin13 content was not statistically different in patients with normal sinus rhythm (NSR) versus atrial fibrillation (AF) (7.85 ± 1.2 ng/μg total protein vs. 8.12 ± 1.5 ng/μg total protein, P = 0.89). (B) By contrast, human atrial PYRapelin13 content was significantly reduced in AF versus NSR (0.29 ± 0.05 ng/mL vs. 0.73 ± 0.2 ng/mL, *P < 0.05). (C) Reverse transcriptase PCR (RT-PCR) for human AJP in both human right atrial appendage (RAA) (blue lanes) and isolated atrial myocytes (green lanes) from patients with NSR yielded the calculated 323 bp fragment in 3 patients. M represents the 100 kb ladder. (D) In 2 independent murine strains, 129SV and C57BL6 homozygous deletion of the apelin gene versus WT controls resulted in intact atrial NADPH oxidase activity, which was approximately 2.4-fold greater (n = 3 animals per group, *P < 0.05). (E) Representative atrial CV isochrones derived from pacing of the left atrial myocardium at pacing cycling lengths from 250 to 80 ms in apelin WT and -KO mice. Ex vivo murine left atrial voltage-sensitive optical mapping microscopy with di-4-ANEPPS revealed a significant decrease in atrial CV in apelin-KO versus WT control mice (n = 4 at 18 months of age, n = 3 at 10 months of age, *P < 0.05 versus WT, +/+). (F) Representative Sirius red staining demonstrating no significant changes in atrial interstitial fibrosis between WT (4.44% ± 1.48%) and apelin-KO mice (6.76% ± 1.46%) (scale bar: 100 mm). RLU, relative light units. Student’s t test, *P < 0.05.