title: Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy is a genetic disease characterized by cardiac hypertrophy, myocyte disarray, interstitial fibrosis, and left ventricular (LV) dysfunction. We have proposed that hypertrophy and fibrosis, the major determinants of mortality and morbidity, are potentially reversible. We tested this hypothesis in beta-myosin heavy chain-Q(403) transgenic rabbits.
  
  
  RESULTS
  We randomized 24 beta-myosin heavy chain-Q(403) rabbits to treatment with either a placebo or simvastatin (5 mg. kg(-1). d(-1)) for 12 weeks and included 12 nontransgenic controls. We performed 2D and Doppler echocardiography and tissue Doppler imaging before and after treatment. Demographic data were similar among the groups. Baseline mean LV mass and interventricular septal thickness in nontransgenic, placebo, and simvastatin groups were 3.9+/-0.7, 6.2+/-2.0, and 7.5+/-2.1 g (P<0.001) and 2.2+/-0.2, 3.1+/-0.5, and 3.3+/-0.5 mm (P=0.002), respectively. Simvastatin reduced LV mass by 37%, interventricular septal thickness by 21%, and posterior wall thickness by 13%. Doppler indices of LV filling pressure were improved. Collagen volume fraction was reduced by 44% (P<0.001). Disarray was unchanged. Levels of activated extracellular signal-regulated kinase (ERK) 1/2 were increased in the placebo group and were less than normal in the simvastatin group. Levels of activated and total p38, Jun N-terminal kinase, p70S6 kinase, Ras, Rac, and RhoA and the membrane association of Ras, RhoA, and Rac1 were unchanged.
  
  
  CONCLUSIONS
  Simvastatin induced the regression of hypertrophy and fibrosis, improved cardiac function, and reduced ERK1/2 activity in the beta-myosin heavy chain-Q(403) rabbits. These findings highlight the need for clinical trials to determine the effects of simvastatin on cardiac hypertrophy, fibrosis, and dysfunction in humans with hypertrophic cardiomyopathy and heart failure.
authors.affiliation: Section of Cardiology, Department of Medicine, The DeBakey Heart Center, The Methodist Hospital and Baylor College of Medicine, Houston, Texas, USA.
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.forename: S F
authors.initials: SF
authors.lastname: Nagueh
authors.forename: N
authors.initials: N
authors.lastname: Tsybouleva
authors.forename: M
authors.initials: M
authors.lastname: Abdellatif
authors.forename: S
authors.initials: S
authors.lastname: Lutucuta
authors.forename: H A
authors.initials: HA
authors.lastname: Kopelen
authors.forename: M A
authors.initials: MA
authors.lastname: Quinones
authors.forename: W A
authors.initials: WA
authors.lastname: Zoghbi
authors.forename: M L
authors.initials: ML
authors.lastname: Entman
authors.forename: R
authors.initials: R
authors.lastname: Roberts
authors.forename: A J
authors.initials: AJ
authors.lastname: Marian
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D004452:Echocardiography; D015150:Echocardiography, Doppler; D004719:Endomyocardial Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D011817:Rabbits; D012074:Remission Induction; D019821:Simvastatin / Q000008:administration & dosage*; D016277:Ventricular Function, Left / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D019821:Simvastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018995:Myosin Heavy Chains; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein