LKB1 Knockout Mouse Develops Spontaneous Atrial Fibrillation and Provides Mechanistic Insights Into Human Disease Process

Abstract

BackgroundAtrial 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 ResultsCardiac‐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.ConclusionsLKB1 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.

Deletion of Lkb1 in adult mice results in body weight reduction and lethality

“…Here we also found that the heart of KO mice appeared larger than that of the Lkb1 flox/flox mice. Consistently, cardiac-specific deletion of Lkb1 resulted in the hypertrophy and dysfunction of heart9 but did not affect the body weight78. Taken together, the reduction of body weight in the TMX-inducible Lkb1 knockout mice may be mainly driven by the Lkb1 deficiency in liver or endothelial cells, and the reduction of fat mass may be a secondary effect of altered systemic energy metabolism.…”

“…Cardiac-specific deletion of Lkb1 causes early defects in atrial channel expression, atrial fibrillation, hypertrophy and heart dysfunction789. Liver-specific deletion of Lkb1 in mice results in defective canaliculi and bile duct formation, hyperglycemia, body weight reduction and death2101112.…”

Aging Modulates the Substrate and Triggers Remodeling in Atrial Fibrillation

“…68 Moreover, cardiomyocyte-specific ablation of liver kinase B1, an activator of AMPK, in a mice model resulted in the development of spontaneous AF and an age-dependent progression of AF from a paroxysmal to a persistent form. 69 Collectively, these findings again suggest the importance of atrial metabolic remodeling in AF.…”

Irregular rhythm and atrial metabolism are key for the evolution of proarrhythmic atrial remodeling in atrial fibrillation

“…However, increased AMPK is traditionally considered a protective factor, improving metabolic disturbances and cellular dysfunction [9]. In agreement, recent work showed that knock-out of liver kinase B1, an activator of AMPK, reduces AMPK activation and results in an age-dependent development of spontaneous AF in mice [21]. Since the present work did not validate whether AMPK inhibition reduces apoptosis under these experimental conditions, AMPK activation might be an adaptive response to AF, with the apoptosis resulting from other pathways activated during AF.…”