Cardiovascular Research Advance Access first published online on June 30, 2009
This version [Corrected Proof] published online on July 17, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp216
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Chronic heart failure and the substrate for atrial fibrillation
1 Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
2 Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA
3 College of Pharmacy, The Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USA
4 College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
5 Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Kanagawa, Japan
6 Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, USA
* Corresponding author. Tel: +1 614 292 1715; fax: +1 614 292 1335. E-mail address: carnes.4{at}osu.edu
Aims: We sought to define the underlying mechanisms for atrial fibrillation (AF) during chronic heart failure (HF).
Methods and results: Preliminary studies showed that 4 months of HF resulted in irreversible systolic dysfunction (n = 9) and a substrate for sustained inducible AF (>3 months, n = 3). We used a chronic (4-month) canine model of tachypacing-induced HF (n = 10) to assess atrial electrophysiological remodelling, relative to controls (n = 5). Left ventricular fractional shortening was reduced from 37.2 ± 0.83 to 13.44 ± 2.63% (P < 0.05). Left atrial (LA) contractility (fractional area change) was reduced from 34.9 ± 7.9 to 27.9 ± 4.23% (P < 0.05). Action potential durations (APDs) at 50 and 90% repolarization were shortened by 
60 and 40%, respectively, during HF (P < 0.05). HF-induced atrial remodelling included increased fibrosis, increased Ito, and decreased IK1, IKur, and IKs (P < 0.05). HF induced increases in LA Kv channel interacting protein 2 (P < 0.05), no change in Kv4.3, Kv1.5, or Kir2.3, and reduced Kir2.1 (P < 0.05). When ICa-L was elicited by action potential (AP) clamp, HF APs reduced the integral of ICa in control myocytes, with a larger reduction in HF myocytes (P < 0.05). ICaL measured with standard voltage clamp was unchanged by HF. Incubation of myocytes with N-acetylcysteine (a glutathione precursor) attenuated HF-induced electrophysiological alterations. LA angiotensin-1 receptor expression was increased in HF.
Conclusion: Chronic HF causes alterations in ion channel expression and ion currents, resulting in attenuation of the APD and atrial contractility and a substrate for persistent AF.
KEYWORDS Heart failure; Arrhythmia (mechanisms); Remodelling; K-channel
Time for primary review: 25 days
These authors contributed equally to this work.
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Cardiovasc Res 2009 84: 180-181.
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  A. C. Rankin and A. J. Workman Duration of heart failure and the risk of atrial fibrillation: different mechanisms at different times? Cardiovasc Res, November 1, 2009; 84(2): 180 - 181. [Full Text] [PDF]
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