Abstract 12682: Increased Histone Methylation in End-stage Cardiomyopathy Under Mechanical Support; Potential Target to Enhance ‰Bridge-to-recovery”
Background Epigenetics alternations, such as acethylation and methylation of the histone, have been proved to be associated with development of a variety of chronic degenerative pathologies, though they were not fully assessed in end-stage cardiomyopathy. We here hypothesized that modulation of histone methylation may influence on the progression of end-stage heart failure.
Methods Nine patients who completed “bridge-to-transplantation” strategy supported by ventricular assist device (VAD) with a median support being 876 days (574 to 1826 days) were included. Transmural tissue of the left ventricle (LV) was sampled at the time of the VAD implant and transplant surgery.
Results Echocardiographically, systolic dimension of the LV was decreased from 62±8 mm to 54±14 mm during the VAD support (P <0.05), while ejection fraction was increased from 15±5% to 24±10% (P <0.05). In addition, BNP level showed decreased from 725.6±590.6pg/ml to 96.0±54.4pg/ml during the VAD support. Immunohistolabeling showed that significantly increased epigenetic alterations in the myocytes over the VAD support included histone H3 lysine 9 (H3K9) di-methylation (56.0% to 66.7% of total myocytes, P < 0.01), H3K9 tri-methylation (63.9% to 73.1% of total myocytes, P < 0.01), and H3 lysine 4 (H3K4) tri-methylation (57.2% to 64.4% of total myocytes, P <0.01). In contrast, H3K4 di-methylation, H3 lysine 27 tri-methylation, histone 4 lysine 20 (H4K20) di-/tri-methylation, H3K9 acethylation or H4K20 acethylation were not significantly changed over the VAD support. Moreover real-time PCR depicted that expression of SUV39H1, which is methyltransferase of H3K9, was significantly increased by 141% over the VAD support. While expression of JMJD2A and 2D, which are demethylase of H3K9, was significantly decreased by 68.4% and 65%, respectively, over the VAD support. Interestingly, the increase of H3K9me3 expression was significantly correlated with BNP levels during the VAD support (R2 = 0.650, P = 0.0087).
Conclusion Methylation of histone (H3K9 di-methylation and H3K9 tri-methylation) was increased under the long-term VAD support, associated with functional recovery, suggesting that histone methylation might be a therapeutic target to enhance “bridge-to-recovery”.
- © 2012 by American Heart Association, Inc.