Activation of AMP-Activated Protein Kinases Prevents Atrial Fibrillation
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ORIGINAL ARTICLE
Activation of AMP-Activated Protein Kinases Prevents Atrial Fibrillation Cevher Ozcan 1,2 & Gunjan Dixit 1 & Zhenping Li 1 Received: 13 May 2020 / Accepted: 13 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Atrial fibrillation (AF) is common, yet there is no preventive therapy for AF. We tested the efficacy of AMP-activated protein kinase (AMPK) activators, metformin, and aspirin, in primary prevention of AF in cardiac-specific liver kinase B1 (LKB1) knockout (KO) mouse model of AF. Incidence of spontaneous AF was significantly reduced in treated KO mice with metformin (10 mg/kg/day) (8.3% in male and 10.3% in female) and aspirin (20 mg/kg/day) (29.4% in male and 21.4% in female) compared with untreated littermates (81% in male and 67% in female) at 8 weeks (p < 0.05). Prevention of AF was associated with activation of AMPK in treated mice and thereby improvement of mitochondrial function, gap junction proteins (connexin 40/ 43), and intra- and inter-cellular ultrastructure in atrial myocardium. Fibrosis was significantly less in treated mice atria. Pharmacological activation of AMPK is an effective upstream therapy for the primary prevention of AF in susceptible heart. Keywords Atrial fibrillation . AMPK . Metformin . Aspirin . Therapeutic intervention . Pharmacotherapy
Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice by affecting 9% of those ≥ 65 years of age living in the USA [1]. It is a major public health problem with an increased risk of all-cause mortality and morbidity including a high risk of stroke, heart failure, dementia, kidney failure, and myocardial infarction and death [1]. AF is a global problem with an estimated 46.3 million patients [2]. Yet, there is no effective upstream therapy for the primary prevention of AF despite the increasing incidence and prevalence of the disease [1]. Mechanisms of AF are complex and include multiple clinical and molecular factors [1–3]. However, there is no
Editor-in-Chief Enrique Lara-Pezzi oversaw the review of this article * Cevher Ozcan [email protected] 1
Department of Medicine, Section of Cardiology, Heart and Vascular Center, University of Chicago Medical Center, Chicago, IL, USA
2
Department of Medicine, Section of Cardiology, Center for Arrhythmia Care, Heart and Vascular Center, The University of Chicago Biological Sciences Division, 5841 S. Maryland Avenue, MC 6080, Chicago, IL 60637, USA
mechanism-based strategy for the prevention of AF disease process in clinical practice. Recently, we and others demonstrated that inhibition of AMP-activated protein kinase (AMPK) activity due to genetic deletion of the upstream kinase, liver kinase B1 (LKB1), initiates and progresses spontaneous AF in mice [4–7]. As a cellular metabolic sensor, AMPK regulates energy metabolism in atrial cardiomyocyte and involves numerous cellular processes including cell growth, autophagy, calcium handling, and metabolic adaptation [4–10]. It is known that exercise an
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