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J Am Heart Assoc. 2015 Mar 15;4(3):e001733. doi: 10.1161/JAHA.114.001733.

LKB1 knockout mouse develops spontaneous atrial fibrillation and provides mechanistic insights into human disease process.

Author information

1
Division of Cardiovascular Medicine, Department of Medicine, Clinical & Translational Research Center, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY (C.O., E.B., R.Y., G.S.) Section of Cardiology, Department of Medicine, University of Chicago, IL (C.O.).
2
Division of Cardiovascular Medicine, Department of Medicine, Clinical & Translational Research Center, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY (C.O., E.B., R.Y., G.S.).

Abstract

BACKGROUND:

Atrial fibrillation (AF) is a complex disease process, and the molecular mechanisms underlying initiation and progression of the disease are unclear. Consequently, AF has been difficult to model. In this study, we have presented a novel transgenic mouse model of AF that mimics human disease and characterized the mechanisms of atrial electroanatomical remodeling in the genesis of AF.

METHODS AND RESULTS:

Cardiac-specific liver kinase B1 (LKB1) knockout (KO) mice were generated, and 47% aged 4 weeks and 95% aged 12 weeks developed spontaneous AF from sinus rhythm by demonstrating paroxysmal and persistent stages of the disease. Electrocardiographic characteristics of sinus rhythm were similar in KO and wild-type mice. Atrioventricular block and atrial flutter were common in KO mice. Heart rate was slower with persistent AF. In parallel with AF, KO mice developed progressive biatrial enlargement with inflammation, heterogeneous fibrosis, and loss of cardiomyocyte population with apoptosis and necrosis. Atrial tissue was infiltrated with inflammatory cells. C-reactive protein, interleukin 6, and tumor necrosis factor α were significantly elevated in serum. KO atria demonstrated elevated reactive oxygen species and decreased AMP-activated protein kinase activity. Cardiomyocyte and myofibrillar ultrastructure were disrupted. Intercellular matrix and gap junction were interrupted. Connexins 40 and 43 were reduced. Persistent AF caused left ventricular dysfunction and heart failure. Survival and exercise capacity were worse in KO mice.

CONCLUSIONS:

LKB1 KO mice develop spontaneous AF from sinus rhythm and progress into persistent AF by replicating the human AF disease process. Progressive inflammatory atrial cardiomyopathy is the genesis of AF, through mechanistic electrical and structural remodeling.

KEYWORDS:

animal models of human disease remodeling; atrial fibrillation; atrium; inflammation; pathogenesis

PMID:
25773299
PMCID:
PMC4392447
DOI:
10.1161/JAHA.114.001733
[Indexed for MEDLINE]
Free PMC Article

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