Abstract 1343: Atrial Cardiomyocyte Tachycardia Alters Cardiac Fibroblast Function: A Novel Consideration in Atrial Remodeling
Background: Atrial fibrillation (AF) produces tachycardia-related changes in atrial electrophys-iology, 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 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 HL1 atrial cardiomyocytes (group 5 Hz), non-paced cardiomyocytes (group NP) and cardiomyocyte pacing medium only (group Ø), and analyzed by [3H]thymidine incorporation, Western-blot and real-time RT-PCR.
Results: Rapidly-paced cardiomyocyte conditioned medium altered fibro-blast proliferation, reducing [3H]thymidine uptake compared to non-paced cardiomyocyte conditioned medium or medium alone (2.1±1.5** vs. 15.9±3.3 and 16.4±4.2 respectively, **P<0.01 vs. both NP and Ø). Rapidly-paced cardiomyocyte conditioned medium increased αSMA protein reflecting an activated myofibroblast phenotype (1.6±0.2** vs 1.1±0.3 and 1.0±0.2), collagen-1 (2.4±0.2* vs. 1.5±0.3 and 1.1±0.2, *P<0.05 vs NP and Ø) and fibronectin-1 (3.1±0.3* vs 1.8±0.45 and 1.2±0.2) mRNA expression compared to controls. Adding the AT1 receptor blocker valsartan to conditioned medium attenuated pacing-induced αSMA increase but had no effect on fibroblast proliferation. Atrial tissue from 1-wk 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 shams.
Conclusions: Rapidly-discharging atrial cardiomyocytes release substances that profoundly alter cardiac fibroblast function, inducing an activated myofibroblast phenotype that is reflected by increased extracellular matrix (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.