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(Circulation Research. 2005;97:285.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Prevention of Cardiac Hypertrophy by Atorvastatin in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy

Vinitha Senthil, Suet N. Chen, Natalie Tsybouleva, Tripti Halder, Sherif F. Nagueh, James T. Willerson, Robert Roberts, A.J. Marian

From the Section of Cardiology (V.S., S.N.C., N.T., T.H., S.F.N., A.J.M.), Department of Medicine, Baylor College of Medicine, Houston, Tex; the University of Texas Health Sciences Center at Houston (J.T.W.), Tex; and the University of Ottawa Heart Institute (R.R.), Ontario, Canada.

Correspondence to Dr A.J. Marian, Associate Professor of Medicine, Section of Cardiology, Baylor College of Medicine, One Baylor Plaza, 519D, Houston, TX 77030. E-mail amarian{at}bcm.tmc.edu

Cardiac hypertrophy, a major determinant of morbidity and mortality in hypertrophic cardiomyopathy (HCM), is considered a secondary phenotype and potentially preventable. To test this hypothesis, we screened 30 5- to 6-month-old ß-myosin heavy chain Q403 transgenic rabbits by echocardiography and selected 26 without cardiac hypertrophy. We randomized the transgenic rabbits to treatment with atorvastatin (2.5 mg/Kg/d), known to block hypertrophic signaling or a placebo. We included 15 nontransgenic rabbits as controls. Cardiac phenotype was analyzed serially before, 6 and 12 months after randomization. Serum total cholesterol levels were reduced by 49% with atorvastatin administration. Left-ventricular mass, wall thickness; myocyte size, myocardial levels of molecular markers of hypertrophy, lipid peroxides, and oxidized mitochondrial DNA; and the number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive myocytes were increased significantly in the placebo but not in the atorvastatin group. Myocardium catalase mRNA levels were decreased by 5-fold in the placebo but were normal in the atorvastatin group. Catalase protein level and activity were not significantly changed. Levels of membrane-bound Ras and phospho-p44/42 mitogen-activated-protein kinase (MAPK) were increased in the placebo group (2.5 fold) but were reduced in the atorvastatin group. Levels of GTP- and membrane-bound RhoA and Rac1, phospho-p38, and phospho-c-Jun NH2-terminal kinases were unchanged. Thus, atorvastatin prevented development of cardiac hypertrophy; determined at organ, cellular, and molecular levels, partly through reducing active Ras and p44/42 MAPK. The results indicate potential beneficial effects of atorvastatin in prevention of cardiac hypertrophy, a major determinant of morbidity in all forms of cardiovascular diseases, and beckon clinical studies in humans with HCM.

Key Words: hypertrophy • genetics • prevention • gene expression • statins

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