Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin

Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only protein (HopXTg), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14–18 weeks): wild-type (WT), HopXTg, HopXTg mice treated with TSA for 2 weeks (TSA-HopX) and wild-type mice treated with TSA for 2 weeks (TSA-WT). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopXTg mice (48 episodes in 13 of 15 HopXTg mice versus 5 episodes in 2 of 15 TSA-HopX mice, P < 0.001; versus 9 episodes in 2 of 15 WT mice, P < 0.001; versus no episodes in any TSA-WT mice, P < 0.001). TSA reduced atrial arrhythmia duration in HopXTg mice (1307 ± 289 ms versus 148 ± 110 ms, P < 0.01) and atrial fibrosis (8.1 ± 1.5% versus 3.9 ± 0.4%, P < 0.001). Atrial connexin40 was lower in HopXTg compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopXTg mice (76.3 ± 26.0 versus 69.7 ± 16.6 pg/mg protein, P = NS). Therefore, it appears HDAC-inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy.