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

ABSTRACT: 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 (HopX(Tg)), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopX(Tg), HopX(Tg) 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 HopX(Tg) mice (48 episodes in 13 of 15 HopX(Tg) 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 HopX(Tg) 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 HopX(Tg) 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 HopX(Tg) 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.

SUBMITTER: Liu F

PROVIDER: S-EPMC2630487 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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

Liu Fang F Levin Mark D MD Petrenko Nataliya B NB Lu Min Min MM Wang Tao T Yuan Li Jun LJ Stout Andrea L AL Epstein Jonathan A JA Patel Vickas V VV

Journal of molecular and cellular cardiology 20080916 6

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 (HopX(Tg)), which recruits HDAC activity to induc ...[more]

PMID: 18926829

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Project description:Renal denervation (RD) was reported to reduce the susceptibility of atrial fibrillation (AF), but the underlying mechanism has not been well understood. This study was performed to investigate the effect of RD on the inducibility of AF in a rabbit model for atrial fibrosis and to explore the potential mechanisms. Thirty-five rabbits were randomly assigned into sham-operated group (n = 12), abdominal aortic constriction (AAC) group (n = 12) and AAC with RD (AAC-RD) group (n = 11). The incidence of AF induced by burst pacing in atriums was determined. Blood was collected to measure the levels of rennin, angiotensin II and aldosterone. Atrial samples were preserved to evaluate protein and gene expression of collagen, connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1). Our data suggested cardiac structure remodeling and atrial fibrosis were successfully induced by AAC. Compared with the AAC group, the AAC-RD rabbits had smaller ascending aortic diameter and left ventricular end-systolic diameter. For burst pacing at the left atrium (LA), AF was induced in two of the 12 rabbits in the sham-operated group, 10 of the 12 rabbits in the AAC group, and 2 of the 11 rabbits in the AAC-RD group, with great difference among the three groups (P = 0.001). The percentage of LA burst stimulations with induced AF achieved 47.2% in the AAC group, which was higher than those in both the AAC-RD (12.1%) and the Sham-operated (5.6%) groups. Significantly increasing intercellular space in the AAC group (P<0.001) compared with the sham-operated rabbits. RD clearly decreased the volume fraction of collagen in LA and right atrium compared with that of the AAC group (P< 0.01). AAC-induced elevation of collagen I, CTGF and TGF-β1 was suppressed by RD. In conclusion, RD suppressed the inducibility of AF in a rabbit model for pressure associated atrial fibrosis, potentially by modulating renin-angiotensin-aldosterone system and decreasing pro-fibrotic factors.

Dataset Information

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

Publications

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

Similar Datasets

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