Abstract
Background: Atrial fibrillation (AF) produces atrial tachycardia-related changes in atrial electrophysiology, providing a possible explanation for the progressive nature of the arrhythmia. Structural remodeling results from ventricular dysfunction due to a rapid response to AF, but whether AF itself can cause atrial fibrosis remains unclear. 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 (group 5Hz), non-paced cardiomyocytes (group NP) and cardiomyocyte pacing medium alone (group Ø), and analyzed by [3H]thymidine incorporation, Western-blot and real-time RT-PCR. 
 Results: Rapidly-paced cardiomyocyte-conditioned medium had a potent anti-proliferative effect, reducing [3H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (2,143±1,490** vs. 15,870±3,343 and 16,440±4,193 respectively, **P < 0.01 vs. both NP and Ø). Conditioned medium from rapidly-paced cardiomyocytes increased αSMA protein reflecting an activated myofibroblast phenotype (1.62±0.20** vs. 1.08±0.26 and 1.01±0.24), collagen-1 (2.41±0.22* vs. 1.49±0.33 and 1.10±0.19, *P < 0.05 both NP and Ø) and fibronectin-1 (3.05±0.28* vs. 1.80±0.45 and 1.20±0.19) mRNA expression compared to control cells. Treatment of the conditioned medium with the AT1 receptor blocker valsartan, partially attenuated the pacing-induced αSMA increase but had no effect on fibroblast proliferation. Atrial tissue from 1-week atrial-tachypaced dogs with AV block/ventricular pacing to control ventricular rate similarly showed upregulation of collagen-1 (2.6±0.5 vs. 0.7±0.3, P < 0.01) and fibronectin-1 (4.9±0.6 vs. 1.1±0.4, P < 0.001) mRNA versus unpaced shams. Conclusion: Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function and induce an activated myofibroblast phenotype that is reflected by altered ECM-gene expression in vivo. These findings are consistent with recent observations that AF per se causes ECM remodeling and may have important consequences for understanding and preventing the mechanisms underlying AF progression.
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