title: Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: a novel consideration in atrial remodeling.
abstract: 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 [(3)H]thymidine incorporation, Western blot and real-time RT-PCR.
  
  
  RESULTS
  Rapidly-paced cardiomyocyte-conditioned medium reduced [(3)H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (approximately 85%, P<0.01). Rapidly-paced cardiomyocyte medium increased alpha SMA protein (approximately 55%, p<0.001), collagen-1 (approximately 85%, P<0.05) and fibronectin-1 (approximately 205%, P<0.05) mRNA expression vs. controls. The angiotensin-1 receptor blocker valsartan attenuated pacing-induced alpha SMA changes but did not affect fibroblast proliferation. Suppression of contraction with blebbistatin did not prevent tachypacing-induced changes in [(3)H]thymidine uptake or alpha 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 alpha SMA protein (approximately 40%, P<0.05), collagen-1 (approximately 380%, P<0.01) and fibronectin-1 (approximately 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.
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada.
authors.forename: Brett
authors.initials: B
authors.lastname: Burstein
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.forename: Angelino
authors.initials: A
authors.lastname: Calderone
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000199:Actins / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D002450:Cell Communication / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D003470:Culture Media / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D013610:Tachycardia / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D024042:Collagen Type I; D003470:Culture Media; D005353:Fibronectins; D006576:Heterocyclic Compounds, 4 or More Rings; D013777:Tetrazoles; C472645:blebbistatin; D000068756:Valsartan; D014633:Valine