Published online before print March 2, 2009, doi: 10.1161/CIRCULATIONAHA.108.790501
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(Circulation. 2009;119:1398-1407.)
© 2009 American Heart Association, Inc.
Heart Failure |
Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms
From the Center for Cardiovascular Genetics, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, and Texas Heart Institute, Houston (R.L., G.R., J.T.W., A.J.M.); Baylor College of Medicine, Houston, Tex (S.N.C.); Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University of Naples, Naples, Italy (S.B.); and Department of Biomedical Engineering, Washington University in St Louis, St Louis, Mo (C.M.R., W.L., J.C., S.A.W., I.R.E.).
Correspondence to Ali J. Marian, MD, Center for Cardiovascular Genetics, 6770 Bertner St, DAC 900A, Houston, TX 77030. E-mail Ali.J.Marian{at}uth.tmc.edu
Received May 4, 2008; accepted January 6, 2009.
Background— Cardiac hypertrophy, the clinical hallmark of hypertrophic cardiomyopathy (HCM), is a major determinant of morbidity and mortality not only in HCM but also in a number of cardiovascular diseases. There is no effective therapy for HCM and generally for cardiac hypertrophy. Myocardial oxidative stress and thiol-sensitive signaling molecules are implicated in pathogenesis of hypertrophy and fibrosis. We posit that treatment with N-acetylcysteine, a precursor of glutathione, the largest intracellular thiol pool against oxidative stress, could reverse cardiac hypertrophy and fibrosis in HCM.
Methods and Results— We treated 2-year-old β-myosin heavy-chain Q403 transgenic rabbits with established cardiac hypertrophy and preserved systolic function with N-acetylcysteine or a placebo for 12 months (n=10 per group). Transgenic rabbits in the placebo group had cardiac hypertrophy, fibrosis, systolic dysfunction, increased oxidized to total glutathione ratio, higher levels of activated thiol-sensitive active protein kinase G, dephosphorylated nuclear factor of activated T cells (NFATc1) and phospho-p38, and reduced levels of glutathiolated cardiac 
-actin. Treatment with N-acetylcysteine restored oxidized to total glutathione ratio, normalized levels of glutathiolated cardiac -actin, reversed cardiac and myocyte hypertrophy and interstitial fibrosis, reduced the propensity for ventricular arrhythmias, prevented cardiac dysfunction, restored myocardial levels of active protein kinase G, and dephosphorylated NFATc1 and phospho-p38.
Conclusions— Treatment with N-acetylcysteine, a safe prodrug against oxidation, reversed established cardiac phenotype in a transgenic rabbit model of human HCM. Because there is no effective pharmacological therapy for HCM and given that hypertrophy, fibrosis, and cardiac dysfunction are common and major predictors of clinical outcomes, the findings could have implications in various cardiovascular disorders.
CLINICAL PERSPECTIVE
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Clinical Summaries
Circulation 2009 119: 1353-1354.[Extract] [Full Text]
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