Dataset Information

Increased Susceptibility to Atrial Fibrillation Secondary to Atrial Fibrosis in Transgenic Goats Expressing Transforming Growth Factor-?1.

ABSTRACT: Large animal models of progressive atrial fibrosis would provide an attractive platform to study relationship between structural and electrical remodeling in atrial fibrillation (AF). Here we established a new transgenic goat model of AF with cardiac specific overexpression of TGF-?1 and investigated the changes in the cardiac structure and function leading to AF.Transgenic goats with cardiac specific overexpression of constitutively active TGF-?1 were generated by somatic cell nuclear transfer. We examined myocardial tissue, ECGs, echocardiographic data, and AF susceptibility in transgenic and wild-type control goats. Transgenic goats exhibited significant increase in fibrosis and myocyte diameters in the atria compared to controls, but not in the ventricles. P-wave duration was significantly greater in transgenic animals starting at 12 months of age, but no significant chamber enlargement was detected, suggesting conduction slowing in the atria. Furthermore, this transgenic goat model exhibited a significant increase in AF vulnerability. Six of 8 transgenic goats (75%) were susceptible to AF induction and exhibited sustained AF (>2 minutes), whereas none of 6 controls displayed sustained AF (P < 0.01). Length of induced AF episodes was also significantly greater in the transgenic group compared to controls (687 ± 212.02 seconds vs. 2.50 ± 0.88 seconds, P < 0.0001), but no persistent or permanent AF was observed.A novel transgenic goat model with a substrate for AF was generated. In this model, cardiac overexpression of TGF-?1 led to an increase in fibrosis and myocyte size in the atria, and to progressive P-wave prolongation. We suggest that these factors underlie increased AF susceptibility.

SUBMITTER: Polejaeva IA

PROVIDER: S-EPMC5065395 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Increased Susceptibility to Atrial Fibrillation Secondary to Atrial Fibrosis in Transgenic Goats Expressing Transforming Growth Factor-β1.

Polejaeva Irina A IA Ranjan Ravi R Davies Christopher J CJ Regouski Misha M Hall Justin J Olsen Aaron L AL Meng Qinggang Q Rutigliano Heloisa M HM Dosdall Derek J DJ Angel Nathan A NA Sachse Frank B FB Seidel Thomas T Thomas Aaron J AJ Stott Rusty R Panter Kip E KE Lee Pamela M PM Van Wettere Arnaud J AJ Stevens John R JR Wang Zhongde Z MacLeod Rob S RS Marrouche Nassir F NF White Kenneth L KL

Journal of cardiovascular electrophysiology 20160830 10

<h4>Introduction</h4>Large animal models of progressive atrial fibrosis would provide an attractive platform to study relationship between structural and electrical remodeling in atrial fibrillation (AF). Here we established a new transgenic goat model of AF with cardiac specific overexpression of TGF-β1 and investigated the changes in the cardiac structure and function leading to AF.<h4>Methods and results</h4>Transgenic goats with cardiac specific overexpression of constitutively active TGF-β1 ...[more]

PMID: 27447370

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Project description:ObjectiveBeta 1-adrenergic receptor autoantibodies (β1ARAbs) have been identified as a pathogenic factor in atrial fibrillation (AF), but the underlying pathogenetic mechanism is not well understood. We assessed the hypothesis that elevated β1ARAb levels increase AF susceptibility by promoting atrial fibrosis.MethodsA total of 70 patients with paroxysmal AF were continuously recruited. The serum levels of β1ARAb and circulating fibrosis biomarkers were analyzed by ELISA. Linear regression was used to examine the correlations of β1ARAb levels with left atrial diameter (LAD) and circulating fibrosis biomarker levels. Furthermore, we established a rabbit β1ARAb overexpression model. We conducted electrophysiological studies and multielectrode array recordings to evaluate the atrial effective refractory period (AERP), AF inducibility and electrical conduction. AF was defined as irregular, rapid atrial beats > 500 bpm for > 1000 ms. Echocardiography, hematoxylin and eosin staining, Masson's trichrome staining, and picrosirius red staining were performed to evaluate changes in atrial structure and detect fibrosis. Western blotting and PCR were used to detect alterations in the protein and mRNA expression of TGF-β1, collagen I and collagen III.ResultsPatients with a LAD ≥ 40 mm had higher β1ARAb levels than patients with a smaller LAD (8.87 ± 3.16 vs. 6.75 ± 1.34 ng/mL, P = 0.005). β1ARAb levels were positively correlated with LAD and circulating biomarker levels (all P < 0.05). Compared with the control group, the rabbits in the immune group showed the following: (1) enhanced heart rate, shortened AERP (70.00 ± 5.49 vs. 96.46 ± 3.27 ms, P < 0.001), increased AF inducibility (55% vs. 0%, P < 0.001), decreased conduction velocity and increased conduction heterogeneity; (2) enlarged LAD and elevated systolic dysfunction; (3) significant fibrosis in the left atrium identified by Masson's trichrome staining (15.17 ± 3.46 vs. 4.92 ± 1.72%, P < 0.001) and picrosirius red staining (16.76 ± 6.40 vs. 4.85 ± 0.40%, P < 0.001); and (4) increased expression levels of TGF-β1, collagen I and collagen III.ConclusionOur clinical and experiential studies showed that β1ARAbs participate in the development of AF and that the potential mechanism is related to the promotion of atrial fibrosis.

Dataset Information

Increased Susceptibility to Atrial Fibrillation Secondary to Atrial Fibrosis in Transgenic Goats Expressing Transforming Growth Factor-?1.

Publications

Increased Susceptibility to Atrial Fibrillation Secondary to Atrial Fibrosis in Transgenic Goats Expressing Transforming Growth Factor-β1.

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