Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation.
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.
Centre for Heart Rhythm Disorders, Discipline of Medicine, University of Adelaide and Department of Cardiology, Royal Adelaide Hospital, Adelaide, Australia.
Hany S
HS
Abed
Chrishan S
CS
Samuel
Dennis H
DH
Lau
Darren J
DJ
Kelly
Simon G
SG
Royce
Muayad
M
Alasady
Rajiv
R
Mahajan
Pawel
P
Kuklik
Yuan
Y
Zhang
Anthony G
AG
Brooks
Adam J
AJ
Nelson
Stephen G
SG
Worthley
Walter P
WP
Abhayaratna
Jonathan M
JM
Kalman
Gary A
GA
Wittert
Prashanthan
P
Sanders
D000704:Analysis of Variance; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D018450:Disease Progression; D019332:Endothelin-1 / Q000378:metabolism; D006325:Heart Atria / Q000503:physiopathology*; D006329:Heart Conduction System / Q000503:physiopathology; D006439:Hemodynamics; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D009765:Obesity / Q000503:physiopathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D012756:Sheep; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015415:Biomarkers; D019332:Endothelin-1; D010982:Platelet-Derived Growth Factor; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor