Grants and Contracts Details
Understanding the mechanisms of cardiac dyssynchrony in obesity: a potential link between obesity and increased cardiovascular mortality Obesity is a modern epidemic and a major health threat to the United States which affects over one third of adults and one fifth of children and adolescents (1). About 200,000 deaths per year are caused by obesity (2), mostly due to cardiovascular disease (3). Dyssynchrony is a condition in which different regions of the heart contract at different times in a dis-coordinated fashion (Fig 1A), and is an independent predictor of cardiac mortality in patients with heart disease (4,5). Preliminary studies have shown that humans with obesity have cardiac dyssynchrony (6,7). We therefore believe it is critical to explore the underlying mechanisms of obesity-related cardiac dyssynchrony to 1) improve our understanding of the obesity epidemic and its link with cardiovascular mortality and 2) ultimately target therapies for reversing cardiac dyssynchrony in this population. Our preliminary data using magnetic resonance imaging (MRI) show for the first time that the mouse model of diet-induced obesity develops cardiac dyssynchrony similar to that seen in humans with obesity (fig 1B). The diet-induced obese mouse is therefore a valuable model for studying the underlying mechanisms of obesity-related cardiac dyssynchrony. We hypothesize that 1) obesity-related cardiac dyssynchrony is due to down regulation and redistribution of the gap junctional protein, connexin 43 (Cx43), and 2) obesity-related cardiac dyssynchrony is reversible through pharmacologic treatment with liraglutide. We will test these hypotheses with the following specific aims: Aim 1: Quantify Cx43 expression and distribution in the left ventricle of mice with diet-induced obesity before and after the onset of cardiac dyssynchrony. Recently, a five-fold down- regulation of Cx43 was reported in an obese mouse model, which may explain the development of cardiac dyssynchrony (8). We will compare Cx43 expression and distribution in the left ventricle in mice before (after 20 weeks on a high-fat diet) and after (after 30 weeks on a high-fat diet) development of dyssynchrony. We will also perform cardiac MRI on these mice to quantify cardiac dyssynchrony. We expect that cardiac dyssynchrony will be increased and Cx43 expression will be significantly reduced after 30 weeks on the high-fat diet compared to the 20-week time point. Aim 2: Investigate reversibility of cardiac dyssynchrony and Cx43 remodeling using liraglutide (an FDA-approved therapy). Liraglutide is a glucagon-like-peptide-1 (GLP- 1) agonist which has been shown to have beneficial effects on cardiac remodeling and dysfunction in the setting of obesity (8). We therefore hypothesize that liraglutide can reverse cardiac dyssynchrony mediated through the Cx43 remodeling. After 30 weeks on a high-fat diet, a group of 20 obese mice will be randomized to receive either liraglutide or placebo. After 4 weeks, we will use cardiac MRI to quantify dyssynchrony and then sacrifice the mice for quantification of Cx43. We expect that the mice given liraglutide will show improvements in cardiac dyssynchrony and Cx43 expression.
|Effective start/end date||7/1/14 → 12/31/14|
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