© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways
aResearch Center, Montreal Heart Institute, Montreal, Quebec, Canada
bDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
cDepartment of Medicine, University of Montreal, Montreal, Quebec, Canada
dDepartment of Pathology, University of Montreal, Montreal, Quebec, Canada
eDepartment of Surgery, University of Montreal, Montreal, Quebec, Canada
*Corresponding author. Medicine and Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8. Tel.: +1-514-376-3330; fax: +1-514-376-1355. Email address: nattel{at}icm.umontreal.ca
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.
KEYWORDS Arrhythmia therapy; Atrial fibrillation; Remodelling
Time for primary review 26 days
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