Elsevier

Heart Rhythm

Volume 10, Issue 1, January 2013, Pages 90-100
Heart Rhythm

Obesity results in progressive atrial structural and electrical remodeling: Implications for atrial fibrillation

https://doi.org/10.1016/j.hrthm.2012.08.043Get rights and content

Background

Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown.

Objective

To examine the effect of progressive weight gain on the substrate for AF.

Methods

Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor.

Results

Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels.

Conclusions

Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.

Introduction

Obesity is recognized to be associated with the development of atrial fibrillation (AF) and has been proposed as a contributor to the expanding epidemic of this arrhythmia.1, 2 Atrial structural and electrical remodeling have been implicated in the AF substrate associated with many conditions predisposing to the development of this arrhythmia3, 4, 5, 6; however, whether weight gain and obesity result in atrial remodeling is not known. Moreover, induction of this substrate along the adiposity spectrum of normal weight to obesity, and its relationship to hemodynamic disturbances, remains unknown. In this study, by using a sheep model of progressive weight gain, we aimed to characterize the atrial functional, structural, and electrophysiological changes accompanying increasing adiposity.

Section snippets

Animals

Thirty-six sheep (Merino Cross Wethers) were studied in accordance with guidelines outlined in the “Position of the American Heart Association on Research Animal Use,” adopted in November 11, 1984. This study was approved by the Animal Ethics Committees of the University of Adelaide and SA Pathology, Adelaide, Australia.

Study protocol

Thirty animals underwent ad libitum feeding to induce obesity, as previously described.7 At baseline, 4 months, and 8 months, 10 of the cohort were randomly selected for cardiac

Results

There was progressive weight gain with feeding duration from 58±7 kg at baseline to 77±5 kg (“overweight”) at 4 months and 105±13 kg (“obese”) at 8 months (P<.001). There was no weight change in the control group: 58±6 kg at baseline, 50±4 kg at 4 months, and 54±5 kg at 8 months (P = .2). Electrolyte, acid-base, and glucose levels remained within normal range throughout the overfeeding process.

Major findings

Progressive weight gain resulted in atrial functional, structural, and electrophysiological remodeling characterized by the following:

  • 1.

    Increased atrial volumes, LA and systemic pressures, ventricular mass, and pericardial fat volumes.

  • 2.

    Increased atrial interstitial fibrosis, inflammation, and myocardial lipidosis.

  • 3.

    Progressive conduction abnormalities with slowing of atrial conduction and increased conduction heterogeneity, which was amplified at shorter coupling intervals and CLs with greater

Conclusions

Progressive obesity predisposes to a greater burden of AF by forming an electropathological substrate. This is disproportionate to the progressive hemodynamic impact of obesity and suggests a direct pathogenic role of obesity on the AF substrate.

Acknowledgments

The authors thank Ms Samar Babkair and Mr Krupesh Patel for their assistance with immunohistochemistry and morphometric analysis, respectively.

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    This article was presented in part by Dr Abed, who was awarded the Ralph Reader Young Investigator Award by the Cardiac Society of Australia and New Zealand. It was published as an abstract in Heart Rhythm 2012;112:S190, Heart Rhythm 2012;93:S183, and Heart Lung and Circulation 2011;20:S2.

    Dr Abed and Dr Mahajan were supported by the Australian Postgraduate Award from the University of Adelaide. Drs Abed and Alasady were supported by the Earl Bakken Electrophysiology Scholarships from the University of Adelaide. Dr Samuel was supported by the RD Wright Fellowship jointly funded by the National Heart Foundation of Australia (NHFA) and the National Health and Medical Research Council (NHMRC) of Australia. Dr Lau was supported by an NHMRC Postdoctoral Fellowship. Dr Alasady was supported by a Postgraduate Scholarship from the NHMRC. Dr Mahajan was supported by the Leo J Mahar Electrophysiology Scholarship from the University of Adelaide. Drs Kuklik, Brooks, and Sanders were supported by the NHFA.

    Dr Sanders served on the advisory board of Bard Electrophysiology, Biosense Webster, Medtronic, St Jude Medical, Merck, and Sanofi-Aventis. He also received lecture fees or research funding from Bard Electrophysiology, Biosense Webster, Medtronic, and St Jude Medical.

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