Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 30, 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, USA, 43210
2 Department of Physiology and Cell Biology
3 College of Pharmacy
4 College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA, 43210
5 Department of Veterinary Medicine, College of Bio resource Sciences, Nihon University, Kanagawa, Japan
6 Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA 32610
Correspondence: Cynthia A. Carnes, Pharm.D., Ph.D., The Ohio State University, College of Pharmacy, 500 W. 12th Ave. Columbus, OH 43210, FAX: 614-292-1335, Phone: 614-292-1715, Email: carnes.4{at}osu.edu
Aims: We sought to define the underlying mechanisms for atrial fibrillation during chronic heart failure (HF). Methods: Preliminary studies showed that 4 months of HF resulted in irreversible systolic dysfunction (n=9) and a substrate for sustained inducible atrial fibrillation (> 3 months, n=3). We used a chronic (4 month) canine model of tachypacing-induced heart failure (n=10) to assess atrial electrophysiologic remodeling, relative to controls (n=5).
Results: Left ventricular fractional shortening was reduced from 37.2±0.83% to 13.44±2.63% (p<0.05). Left atrial contractility (fractional area change) was reduced from 34.9±7.9 to 27.9±4.23% (p<0.05). Action potential durations (APD) at 50 and 90% repolarization were shortened by 
60% and 40%, respectively, during heart failure (p<0.05). Heart failure-induced atrial remodeling included increased fibrosis, increased Ito and decreased IK1, IKur and IKs (p<0.05). Heart failure induced increases in left atrial 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 ICaL was elicited by action potential clamp, heart failure action potentials reduced the integral of ICa in control myocytes, with a larger reduction in heart failure myocytes (p<0.05). ICaL measured with standard voltage clamp was unchanged by heart failure. Incubation of myocytes with N-acetylcysteine (glutathione precursor) attenuated HF-induced electrophysiologic alterations. Left atrial angiotensin-1 receptor expression was increased in heart failure.
Conclusions: Chronic heart failure causes alterations in ion channel expression and ion currents, resulting in attenuation of the APD and atrial contractility and a substrate for persistent atrial fibrillation.
KEYWORDS heart failure; arrhythmia (mechanisms); remodeling; K-channel
Time for primary review: 25 Days
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Cardiovasc Res 2009 84: 180-181.
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