Atrial fibrosis, atrial fibrillation susceptibility, and molecular remodeling in female goats with cardiac TGF-β1 overexpression

Atrial Fibrillation (AF) is the most common cardiac arrhythmia in adult humans. Atrial fibrosis plays a primary role in developing and sustaining this disease phenotype. Specifically, TGF-β1, a potent pro-fibrotic molecule, is implicated in cell turnover, increasing the amount of extracellular matrix in the heart. This increase leads to aberrant electrical signaling and can produce AF. In this study, we hypothesized that TGF-β1 modulates AF susceptibility in TGF-β1 transgenic goats and that genes related to TGF-β1 and AF would be differentially expressed when compared to wild-type (WT) controls. Transgenic (TG) female goats expressing the active form of human TGF-β1 under the control of the cardiac-specific α-myosin heavy chain (α-MHC) promoter and age-matched wild-type female goats were utilized in the study. Pacemakers were implanted in all animals for continuous arrhythmia monitoring and AF inducibility, which was evaluated using five separate 10 s bursts of atrial pacing (200-160 ms). Tissue samples were collected from both atria of TG and WT goats. RNA was extracted, and gene expression analyses were run on a selected panel of genes. Immunohistochemistry was performed on atrial tissue to evaluate for the presence of selected inflammatory markers to elucidate AF substrate in these animals. There was a significant increase in AF inducibility in both frequency and duration in TGF-β1 goats compared to their WT counterparts. There was no significant difference in the number of inflammatory cells tested by immunohistochemistry. Differentially expressed genes between the TG and WT groups were found in several functional categories including AF, apoptosis, extracellular matrix, inflammation, and TGF-β1.These data support the hypothesis that fibrosis is an important modulator of AF susceptibility. More specifically, an overexpression of TGF-β1 significantly increases expression levels of ECM proteins and TGF-β1 signaling modulators, adding to elevated AF risk without altering underlying inflammation.