Copyright © 2007, European Society of Cardiology
Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling*
aDepartment of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada
bDepartment of Physiology, Montreal Heart Institute and Université de Montréal, Montreal, Canada
cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Canada
*Corresponding author. 5000 Belanger St. E., Montreal H1T 1C8, Quebec, Canada. Tel.: +1 514 376-3330; fax: +1 514 376 1355. stanley.nattel{at}icm-mhi.org
Objective Atrial fibrillation (AF) causes tachycardia-induced atrial electrical remodeling, contributing to the progressive nature of the arrhythmia. Ventricular dysfunction due to a rapid response to AF can cause structural remodeling, but whether AF itself directly promotes atrial fibrosis is controversial. This study investigated the hypothesis that rapid atrial cardiomyocyte activation produces factors that influence atrial fibroblast proliferation and secretory functions.
Methods Cultured canine atrial fibroblasts were treated with medium from rapidly-paced atrial cardiomyocytes, non-paced cardiomyocytes and cardiomyocyte-pacing medium only, and analyzed by [3H]thymidine incorporation, Western blot and real-time RT-PCR.
Results Rapidly-paced cardiomyocyte-conditioned medium reduced [3H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (
85%, P<0.01). Rapidly-paced cardiomyocyte medium increased 
SMA protein (55%, p<0.001), collagen-1 (85%, P<0.05) and fibronectin-1 (205%, P<0.05) mRNA expression vs. controls. The angiotensin-1 receptor blocker valsartan attenuated pacing-induced SMA changes but did not affect fibroblast proliferation. Suppression of contraction with blebbistatin did not prevent tachypacing-induced changes in [3H]thymidine uptake or SMA upregulation, pointing to a primary role of electrical over mechanical cardiomyocyte activity. Atrial tissue from 1-week atrial-tachypaced dogs with ventricular rate control similarly showed upregulation of SMA protein (40%, P<0.05), collagen-1 (380%, P<0.01) and fibronectin-1 (430%, P<0.001) mRNA versus shams.
Conclusions Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function, inducing an activated myofibroblast phenotype that is reflected by increased ECM-gene expression in vivo. These findings are consistent with recent observations that AF per se may cause ECM remodeling, and have potentially important consequences for understanding and preventing the mechanisms underlying AF progression.
KEYWORDS Fibrosis; Remodeling; Extracellular matrix; Angiotensin
* Supported by the Canadian Institutes of Health Research.
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