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Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation
Kevin N. Su, … , Fadi G. Akar, Lawrence H. Young
Kevin N. Su, … , Fadi G. Akar, Lawrence H. Young
Published April 22, 2022
Citation Information: JCI Insight. 2022;7(8):e141213. https://doi.org/10.1172/jci.insight.141213.
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Research Article Cardiology

Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation

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Abstract

Metabolic stress is an important cause of pathological atrial remodeling and atrial fibrillation. AMPK is a ubiquitous master metabolic regulator, yet its biological function in the atria is poorly understood in both health and disease. We investigated the impact of atrium-selective cardiac AMPK deletion on electrophysiological and structural remodeling in mice. Loss of atrial AMPK expression caused atrial changes in electrophysiological properties and atrial ectopic activity prior to the onset of spontaneous atrial fibrillation. Concomitant transcriptional downregulation of connexins and atrial ion channel subunits manifested with delayed left atrial activation and repolarization. The early molecular and electrophysiological abnormalities preceded left atrial structural remodeling and interstitial fibrosis. AMPK inactivation induced downregulation of transcription factors (Mef2c and Pitx2c) linked to connexin and ion channel transcriptional reprogramming. Thus, AMPK plays an essential homeostatic role in atria, protecting against adverse remodeling potentially by regulating key transcription factors that control the expression of atrial ion channels and gap junction proteins.

Authors

Kevin N. Su, Yina Ma, Marine Cacheux, Zeki Ilkan, Nour Raad, Grace K. Muller, Xiaohong Wu, Nicole Guerrera, Stephanie L. Thorn, Albert J. Sinusas, Marc Foretz, Benoit Viollet, Joseph G. Akar, Fadi G. Akar, Lawrence H. Young

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Figure 1

Atrium-selective deletion of AMPK leads to atrial fibrillation in mice.

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Atrium-selective deletion of AMPK leads to atrial fibrillation in mice.
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AMPK expression and the development of atrial fibrillation in AMPK double-KO sarcolipin-Cre Prkaa1fl/fl Prkaa2fl/fl (AMPK-dKO) compared with littermate control Prkaa1fl/fl Prkaa2fl/fl (CON) mice. (A) Representative immunoblots with antibodies recognizing the AMPK α2 subunit, both α1 and α2 AMPK subunits (AMPKα), the downstream AMPK target acetyl-CoA carboxylase (ACC), and the phosphorylated form of ACC (pACC) in the left atria (LA), right atria (RA), and left ventricle. (B) Corresponding densitometric quantification of the immunoreactive bands. Values are mean ± SEM of n = 6–8 per group. **P < 0.01, ***P < 0.001 versus CON by unpaired Student’s t test. (C) Representative in vivo ECG (lead II) tracings showing normal sinus rhythm in a CON and atrial fibrillation in an atrial AMPK-dKO mouse at 6 weeks of age. Insets show magnified views that demonstrate highly organized atrial P-wave electrical activity in CON and course fibrillatory waves in AMPK-dKO mice. Scale bars: 100 ms. (D) Kaplan-Meier analysis showing the 6-month event-free survival from atrial fibrillation in CON (n = 18) versus AMPK-dKO mice (n = 23), P < 0.001. (E) Graphs show heart rate variability in representative examples of CON mice in sinus rhythm and AMPK-dKO mice in atrial fibrillation, comparing sequential R-R intervals during 60-second recordings (n = 533 intervals for CON and n = 454 intervals for AMPK-dKO mice).

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ISSN 2379-3708

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