title: A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice.
abstract: Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Green
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Anderson
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Evanchik
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Gorham
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Brooke C
authors.initials: BC
authors.lastname: Harrison
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Henze
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Kawas
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Johan D
authors.initials: JD
authors.lastname: Oslob
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Hector M
authors.initials: HM
authors.lastname: Rodriguez
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wan
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Spudich
authors.affiliation: MyoKardia, South San Francisco, CA 94080, USA. cseidman@genetics.harvard.edu rmcdowell@myokardia.com.
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. cseidman@genetics.harvard.edu rmcdowell@myokardia.com.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage* / Q000737:chemistry; D024722:Cardiac Myosins / Q000037:antagonists & inhibitors* / Q000235:genetics; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018995:Myosin Heavy Chains / Q000037:antagonists & inhibitors* / Q000235:genetics; D051381:Rats; D012518:Sarcomeres / Q000187:drug effects*; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D001596:Benzylamines; C000605992:MYK-461; D014498:Uracil; D000251:Adenosine Triphosphatases; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains