Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis

Journal of Obesity, Sep 2016

Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules. Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR. Obese rats had significant upregulation of , HCN4, , RYR2, NCX1, SERCA2a, and RYR2 mRNA and downregulation of ERG mRNA. In the case of HCN4, it was confirmed that there was a significant increase in protein expression. The potential effects of the mRNA changes on the ventricular action potential and intracellular Ca2

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Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis

Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis Reza Ashrafi,1 Marianne Yon,1 Lucy Pickavance,1 Joseph Yanni Gerges,2 Gershan Davis,1 John Wilding,1 Kun Jian,3 Henggui Zhang,3 George Hart,2 and Mark Boyett2 1Department of Obesity & Endocrinology, Institute of Ageing and Chronic Disease, Faculty of Health & Life Sciences, University of Liverpool, 4th Floor, UCD, Duncan Building, Daulby Street, Liverpool L69 3GA, UK 2Institute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK 3Biological Physics Group, School of Physics & Astronomy, University of Manchester, Schuster Building, Oxford Road, Manchester M13 9PL, UK Received 7 February 2016; Revised 29 June 2016; Accepted 21 July 2016 Academic Editor: Aron Weller Copyright © 2016 Reza Ashrafi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules. Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR. Obese rats had significant upregulation of , HCN4, , RYR2, NCX1, SERCA2a, and RYR2 mRNA and downregulation of ERG mRNA. In the case of HCN4, it was confirmed that there was a significant increase in protein expression. The potential effects of the mRNA changes on the ventricular action potential and intracellular Ca2+ transient were predicted using computer modelling. Modelling predicted prolongation of the ventricular action potential and an increase in the intracellular Ca2+ transient, both of which would be expected to be arrhythmogenic. Conclusion. High-fat diet causing obesity results in arrhythmogenic cardiac gene expression of ion channels and related molecules. 1. Introduction Obesity is an important developing health issue worldwide and the percentage of people classified as obese (BMI > 30 kg/m2) has more than doubled in the last half century [1], which has significant potential consequences for the cardiovascular health of the population. The process by which individuals become obese is a multifactorial one with consumption of a diet with an excessive energy content arising mainly from high levels of refined carbohydrates and saturated fats, combined with a reduced level of physical activity, a common observation in epidemiological studies [2]. While, in a heterogeneous population, obese individuals will vary in whether their diet contains a higher proportion of saturated fats or refined carbohydrates, there are many studies reporting that diets rich in saturated fats lead to obesity [3]. Obesity is linked to an increased likelihood of atrial [4] and ventricular [5] arrhythmias and sudden cardiac death [6]. The mechanisms responsible for the increase in arrhythmias are not understood. In obese individuals who succumbed to sudden cardiac death, an increase in ventricular ectopy has been observed, which in many cardiac disease states is linked to prolonged ventricular arrhythmias and death [7]. An increase in the corrected QT interval in obese individuals has been observed [8] and an increase in the QT interval is a common finding in many arrhythmogenic disorders. The increase in the QT interval has been suggested to be the result of high levels of circulating fatty acids interfering with ventricular repolarization [9]. However, the increase in the QT interval could also be the result of changes in ventricular ion channel expression. For example, in heart failure, there are changes in ventricular ion channel expression and an increase in the QT interval and ventricular arrhythmias [10]. The rationale behind this study is as follows: in light of the rapidly increasing number of obese patients in many countries, there is a lack of data on the potential mechanisms for the higher rates of arrhythmias seen in obese patients when compared to other conditions associated with arrhythmias such as channelopathies where mechanisms are well researched and understood. The objective of this study as part of a wider study into the effects of dietary obesity was to gain an insight into some of the potential mechanisms underlying obesity-induced arrhythmogenesis by investigating the expression of a variety of key cardiac ion channels (and related molecules) in a rat model of obesity based on high saturated (...truncated)


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Reza Ashrafi, Marianne Yon, Lucy Pickavance, Joseph Yanni Gerges, Gershan Davis, John Wilding, Kun Jian, Henggui Zhang, George Hart, Mark Boyett. Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis, Journal of Obesity, 2016, 2016, DOI: 10.1155/2016/7127898