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Activation of AMP-Activated Protein Kinases Prevents Atrial Fibrillation

Cevher Ozcan1,2, Gunjan Dixit3, Zhenping Li3

  • 1Department of Medicine, Section of Cardiology, Heart and Vascular Center, University of Chicago Medical Center, Chicago, IL, USA. cozcan@uchicago.edu.

Journal of Cardiovascular Translational Research
|August 27, 2020
PubMed

Insights

Metformin and aspirin effectively prevent atrial fibrillation (AF) in a mouse model by activating AMP-activated protein kinase (AMPK). This approach improves heart cell structure and function, offering a potential preventive therapy for AF.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Atrial fibrillation (AF) is a prevalent cardiac arrhythmia with no current preventive therapies.
  • AMP-activated protein kinase (AMPK) plays a crucial role in cellular energy homeostasis and has been implicated in cardiac function.

Purpose of the Study:

  • To investigate the efficacy of AMPK activators, metformin and aspirin, in the primary prevention of AF.
  • To explore the underlying mechanisms of AF prevention by AMPK activation in a cardiac-specific LKB1 knockout mouse model.

Main Methods:

  • Utilized a cardiac-specific LKB1 knockout mouse model engineered for AF susceptibility.
  • Administered metformin (10 mg/kg/day) and aspirin (20 mg/kg/day) to assess AF incidence over 8 weeks.
  • Analyzed AMPK activation, mitochondrial function, gap junction protein expression (connexin 40/43), and atrial tissue ultrastructure and fibrosis.

Main Results:

  • Metformin and aspirin significantly reduced spontaneous AF incidence in knockout mice compared to untreated controls (e.g., metformin reduced AF to 8.3% in males and 10.3% in females).
  • AF prevention correlated with increased AMPK activation, improved mitochondrial function, enhanced gap junction protein expression, and better atrial myocardium ultrastructure.
  • Significantly reduced fibrosis was observed in the atria of treated mice.

Conclusions:

  • Pharmacological activation of AMPK serves as an effective upstream therapeutic strategy for the primary prevention of AF.
  • Metformin and aspirin demonstrate potential as preventive agents for AF in susceptible individuals by targeting AMPK pathways.
  • AMPK activation ameliorates AF pathophysiology through improvements in mitochondrial function, cardiac cell structure, and reduced fibrosis.
Keywords:
AMPKAspirinAtrial fibrillationMetforminPharmacotherapyTherapeutic intervention

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