LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation. (7th September 2015)

• Record Type: Journal Article
• Authors: Kim, Grace E.; Ross, Jenna L.; Xie, Chaoqin; Su, Kevin N.; Zaha, Vlad G.; Wu, Xiaohong; Palmeri, Monica; Ashraf, Mohammed; Akar, Joseph G.; Russell, Kerry S.; Akar, Fadi G.; Young, Lawrence H.
• Is Part Of: Cardiovascular research. Volume 108:Number 1(2015)
• Page Start: 197
• Page End: 208
• Publication Date: 2015-09-07
• Subjects: Atrial fibrillation -- Cellular signalling pathways -- LKB1; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvv212
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Liver kinase B1 (LKB1) is a protein kinase that activates the metabolic regulator AMP-activated protein kinase (AMPK) and other related kinases. Deletion of LKB1 in mice leads to cardiomyopathy and atrial fibrillation (AF). However, the specific role of the LKB1 pathway in early atrial biology remains unknown. Thus, we investigated whether LKB1 deletion altered atrial channel expression and electrophysiological function in a cardiomyocyte-specific knockout mouse model. Methods and results: We performed a systematic comparison of αMHC-Cre LKB1 fl/fl and littermate LKB1 fl/fl male mice. This included analysis of gene expression, histology, and echocardiography, as well as cellular and tissue-level electrophysiology using patch-clamp recordings in vitro, optical mapping ex vivo, and ECG recordings in vivo . At postnatal day 1, atrial depolarization was prolonged, and Nav 1.5 and Cx40 expression were markedly down-regulated in MHC-Cre LKB1 fl/fl mice. Inward sodium current density was significantly decreased in MHC-Cre LKB1 fl/fl neonatal atrial myocytes. Subsequently, additional alterations in atrial channel expression, atrial fibrosis, and spontaneous onset of AF developed by 2 weeks of age. In adult mice, abnormalities of interatrial conduction and bi-atrial electrical coupling were observed, likely promoting the perpetuation of AF. Mice with AMPK-inactivated hearts demonstrated modest overlap in channel expression with MHC-Cre LKB1 fl/fl hearts, but retained normal structure, electrophysiological function and contractility. Conclusions: Deletion of LKB1 causes early defects in atrial channel expression, action potential generation and conduction, which precede widespread atrial remodelling, fibrosis and AF. LKB1 is critical for normal atrial growth and electrophysiological function.