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Circulation Research. 2004
Published online before print April 29, 2004, doi: 10.1161/01.RES.0000129579.59664.9d
A more recent version of this article appeared on June 11, 2004
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Submitted on December 1, 2003
Revised on April 12, 2004
Accepted on April 15, 2004

Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF{beta}-1

Sander Verheule ; Toshiaki Sato ; Thomas Everett IV ; Steven K. Engle ; Dan Otten ; Michael Rubart-von der Lohe ; Hisako O. Nakajima ; Hidehiro Nakajima ; Loren J. Field ; and Jeffrey E. Olgin *

From Krannert Institute of Cardiology (S.V., S.K.E., D.O.), Indiana University School of Medicine, Indianapolis, Ind; Cardiac Electrophysiology (T.S., T.E., J.E.O.), Division of Cardiology and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, Calif; Herman B. Wells Center for Pediatric Research (M.R.-v.d.L., H.O.N., H.N., L.J.F.), Indiana University School of Medicine, Indianapolis, Ind.

* To whom correspondence should be addressed. E-mail: olgin{at}medicine.ucsf.edu.

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.
Key words: atrial fibrillation • fibrosis • growth factors




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