Abstract 16697: Cardiac Specific Overexpression of Transforming Growth Factor β1 (TGF-β1) Increases Susceptibility to Atrial Fibrillation in Transgenic Goats
Introduction: TGF-β1 has a potent profibrotic function and is central to signaling cascades involved in interstitial fibrosis. We assessed the hypothesis that overexpression of myocardial TGF-β1 will promote atrial fibrosis in transgenic goats, which would lead to an increased susceptibility to atrial fibrillation (AF).
Methods and results: Three transgenic goats (#1, 2 and 3), expressing human TGF-β1cys33ser (hTGF-β1) under control of the cardiac-specific α-MHC promoter, were generated by somatic cell nuclear transfer. Under intracardiac echocardiogram visualization and fluoroscopic guidance cardiac biopsies were obtained from the ventricular septum. Skeletal muscle biopsies were also collected from each of the animals. Analysis of gene expression revealed that goat #1 had higher cardiac hTGF-β1 expression than goat #2 and that goat #3 had no detectable hTGF-β1 mRNA. None of the goats expressed hTGF-β1 in the skeletal muscle. Different levels of cardiac gene expression are not surprising as random integration was used for the production of the 3 transgenic founder animals. Additionally, a 2 to 3.5-fold increase in cardiac expression of collagen 1 and 3 was observed in goat #1. AF inducibility testing was performed on seven animals (Goats #1, #2 and #3, and 4 control animals) using rapid pacing at 50 Hz for 30 sec at three different locations in the right atrium. Sustained AF was defined as an episode of AF lasting more then 30 seconds. Three out of four AF inducibility test resulted in sustained AF episodes in goat #1. The first AF episode converted to sinus rhythm after 3 min 15 sec. The other two lasted 12 and 16 minutes requiring cardioversion. None of the control animals developed AF following the AF induction test.
Conclusions: The increase in cardiac collagen level in the hTFG-β1 transgenic model is indicative of fibrosis initiation. The data suggest that there is a relationship between the level of hTGF-β1 expression and susceptibility to AF induction in this goat model. This model of hTGF-β1 overexpression represents a dramatic step forward in the development of large animal models, which will allow monitoring the gradual progression of cardiac fibrosis and fibrosis-associated pathologies in a heart similar in size and physiology to the human heart.
- © 2013 by American Heart Association, Inc.