Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling

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 αSMA 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 αSMA changes but did not affect fibroblast proliferation. Suppression of contraction with blebbistatin did not prevent tachypacing-induced changes in [³H]thymidine uptake or αSMA 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 αSMA 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.