title: Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways.
abstract: OBJECTIVE
  Augmented atrial apoptosis, angiotensin II expression, and related signalling pathway activation have been shown in clinical atrial fibrillation (AF), but their significance is poorly understood. This study evaluated temporal relationships between changes in atrial histopathology, selected signalling mediators, and AF promotion, as well as effects of angiotensin-converting enzyme (ACE) inhibition, in a canine model of congestive heart failure (CHF).
  
  
  METHODS
  Dogs were subjected to ventricular tachypacing (VTP) for varying periods up to 5 weeks. Apoptosis was assessed by terminal dUTP nick-end labelling (TUNEL) and DNA fragmentation. Protein expression was determined by Western blot, angiotensin II concentration by ELISA (tissue) and radioimmunoassay (plasma), and caspase-3 activity by enzymatic assay. Histopathological analyses were used to quantify fibrosis, inflammation, and cell death.
  
  
  RESULTS
  Significant apoptosis developed 24 h after VTP onset and persisted for 1 week, returning to baseline thereafter. Apoptosis was preceded by increases in tissue (but not plasma) angiotensin II concentration; enhanced expression of phosphorylated mitogen-activated protein (MAP) kinases p38, JNK, and ERK; and augmented ratios of the proapoptotic protein Bax to the antiapoptotic protein Bcl-2. Increased cell death, leukocyte infiltration, and caspase-3 activity occurred at the time of peak apoptosis. Apoptosis was followed by interstitial fibrosis, which peaked at 5 weeks. ACE inhibition (enalapril) prevented increases in tissue angiotensin II concentration, phosphorylated ERK expression, Bax/Bcl-2 ratio, and cellular apoptosis, but did not affect total cell death, leukocyte infiltration, JNK or p38 activation, and reduced but did not eliminate tissue fibrosis.
  
  
  CONCLUSIONS
  AF-promoting atrial structural remodeling in experimental CHF involves angiotensin II-dependent and angiotensin II-independent pathways. Significant apoptosis occurs, but prevention of apoptosis by ACE inhibition only partially prevents atrial structural remodeling.
authors: Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.
authors: Sophie
authors: S
authors: Cardin
authors: Danshi
authors: D
authors: Li
authors: Nathalie
authors: N
authors: Thorin-Trescases
authors: Tack-Ki
authors: TK
authors: Leung
authors: Eric
authors: E
authors: Thorin
authors: Stanley
authors: S
authors: Nattel
mesh_terms: D000804:Angiotensin II / Q000032:analysis / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001281:Atrial Fibrillation / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D002304:Cardiac Pacing, Artificial; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D053938:DNA Fragmentation; D004285:Dogs; D004656:Enalapril / Q000627:therapeutic use; D006325:Heart Atria / Q000737:chemistry / Q000473:pathology; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051028:bcl-2-Associated X Protein
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; D004656:Enalapril; D020929:Mitogen-Activated Protein Kinase Kinases; D053148:Caspase 3; D020169:Caspases