Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-β1

Abstract

Abstract-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-TGFcys 33 ser 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 (PϽ0.01). 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 Ⅲ fibrosis Ⅲ growth factors A trial fibrillation (AF) is a commonly occurring arrhythmia, present in Ϸ5% of people older than age 65 years. Clinically, increased vulnerability to AF is also associated with underlying heart disease, such as congestive heart failure (CHF) and mitral valve disease. 1 Increased inducibility of AF has been observed in animal models of aging, 2,3 CHF, 4 atrial tachycardia-induced cardiomyopathy, 5,6 and chronic atrial dilatation caused by mitral regurgitation. 7 Theoretical models have implicated atrial interstitial fibrosis as a substrate for AF. 8,9 Atrial interstitial fibrosis increases with age in humans and has been observed in patients with AF 10,11 and in animal models of aging, 2,3 mitral regurgitation, 7 and CHF. 4 With the unknown cause of atrial fibrosis in humans and the presence of compounding factors in animal models, the contribution of atrial fibrosis to AF substrate formation remains unclear. Studies to date have been limited by lack of animal models of selective atrial fibrosis to study the effects of fibrosis without the presence of heart failure or other underlying heart disease.The purpose of this study was to determine the effect of atrial fibrosis on the AF vulnerability. We have studied a transgenic mouse model with cardiac overexpression of a constitutively active form of transforming growth factor (TGF)-␤1, MHC-TGFcys 33 ser. 12 This model has been previously demonstrated to have elevated TGF-␤1 activity in the atria and ventricles. Cardiac development and morphology appear normal, except for increased interstitial fibrosis in the atrial myocardium. Ventricular size and histology is no...

The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction

“…TGF has been shown to be critical in cardiac fibrosis in various experimental models (Lijnen et al, 2000), and inhibition of TGF in such models prevents fibrosis (Teekakirikul et al, 2010). Myocardial overexpression of TGF1 induces atrial, but not ventricular fibrosis (Nakajima et al, 2000;Verheule et al, 2004). Possibly, this remarkable difference in fibrotic response between atria and ventricles is caused by the abundance of CCN2 in atria, which may enhance the effects of TGF (Daniels et al, 2009).…”

Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

“…Nevertheless, it has been reported that the mouse atria are able to sustain fibrillation 14,17,25,26 . Thus, despite the small sizes of mouse atria, our knockout mouse allowed for the investigation of the mechanisms underlying the genesis and maintenance of AF.…”

Gene Therapy for Repair of Cardiac Fibrosis

“…13,14 Finally, a recent transgenic mouse model demonstrated that in the presence of atrial fibrosis, even very small atria can fibrillate. 15 Although fibroblasts are generally considered to be classic examples of nonexcitable cells, in cultured monolayers, some are able to generate and propagate action potentials. These action potentials are based on activation of L-type calcium channels and propagate very slowly (Ͻ0.01 m/s).…”