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(Circulation. 2006;113:2579-2588.)
© 2006 American Heart Association, Inc.

Heart Failure

Suppression of Class I and II Histone Deacetylases Blunts Pressure-Overload Cardiac Hypertrophy

Yongli Kong, MD, PhD; Paul Tannous, BS; Guangrong Lu, MD; Kambeez Berenji, MD; Beverly A. Rothermel, PhD; Eric N. Olson, PhD; Joseph A. Hill, MD, PhD

From the Donald W. Reynolds Cardiovascular Clinical Research Center (E.N.O., J.A.H.) and the Departments of Internal Medicine (Y.K., P.T., G.L., K.B., B.A.R., J.A.H.) and Molecular Biology (E.N.O., J.A.H.), University of Texas Southwestern Medical Center, Dallas.

Correspondence to Joseph A. Hill, MD, PhD, Division of Cardiology, UT Southwestern Medical Center, NB11.200, 6000 Harry Hines Blvd, Dallas, TX 75390–8573. E-mail joseph.hill{at}UTSouthwestern.edu

Received November 21, 2005; de novo received March 7, 2006; revision received April 1, 2006; accepted April 7, 2006.

Background— Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. In cell culture models of cardiac hypertrophy, pharmacological suppression of histone deacetylases (HDACs) can either blunt or amplify cell growth. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophic heart disease.

Methods and Results— In the present investigation, we studied 2 broad-spectrum HDAC inhibitors in a physiologically relevant banding model of hypertrophy, observing dose-responsive suppression of ventricular growth that was well tolerated in terms of both clinical outcome and cardiac performance measures. In both short-term (3-week) and long-term (9-week) trials, cardiomyocyte growth was blocked by HDAC inhibition, with no evidence of cell death or apoptosis. Fibrotic change was diminished in hearts treated with HDAC inhibitors, and collagen synthesis in isolated cardiac fibroblasts was blocked. Preservation of systolic function in the setting of blunted hypertrophic growth was documented by echocardiography and by invasive pressure measurements. The hypertrophy-associated switch of adult and fetal isoforms of myosin heavy chain expression was attenuated, which likely contributed to the observed preservation of systolic function in HDAC inhibitor–treated hearts.

Conclusions— Together, these data suggest that HDAC inhibition is a viable therapeutic strategy that holds promise in the treatment of load-induced heart disease.

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