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

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

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 2

Cardiac structural remodeling in mice with atrial AMPK deletion.

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Cardiac structural remodeling in mice with atrial AMPK deletion. Echocar...
Echocardiogram and CT parameters were analyzed in AMPK double-KO sarcolipin-Cre Prkaa1fl/fl Prkaa2fl/fl (AMPK-dKO) and littermate control Prkaa1fl/fl Prkaa2fl/fl (CON) mice. (A) Serial echocardiographic measurements were performed between 4 and 12 weeks of age; graphs show left atrial (LA) area, left ventricular inner diameter at end-diastole (LVID), LV posterior wall thickness (LVPW), LV ejection fraction (LVEF), and heart rate (HR). Values are mean ± SEM, n = 6–9 per group. (B) Serial cardiac in vivo micro-CT imaging with contrast enhancement performed between 4 and 15 weeks of age. In representative examples of hearts of 4- and 15-week-old mice, the left panels show grayscale horizontal long axis CT cardiac images, and the right panels demonstrate color 3D segmentation reconstructions of the hearts. CT image acquisition was gated to the ECG cycle and was segmented into 8 phases. Images from atrial diastole (LV end-systole) are shown to visualize the fully filled atria. (C) Quantification of cardiac chamber volumes and ventricular ejection fractions (LVEF and RVEF) in mice imaged serially at 4, 8, and 15 weeks of age. Volumes in the fully filled atria (end of LV systole) and ventricles (end of LV diastole) are shown in the graphs. Values are mean ± SEM of n = 9–11 per group. *P < 0.05, **P < 0.01 versus matched controls by 2-way ANOVA with Holm-Šidák multiple-comparison test.