title: Irreversible triggers for hypertrophic cardiomyopathy are established in the early postnatal period.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein genes, and left ventricular hypertrophy (LVH) develops as an adaptive response to sarcomere dysfunction. It remains unclear whether persistent expression of the mutant gene is required for LVH or whether early gene expression acts as an immutable inductive trigger.
  
  
  OBJECTIVE
  The aim of this study was to use a regulatable murine model of HCM to study the reversibility of pathological LVH.
  
  
  METHODS
  The authors generated a double-transgenic mouse model, tTAxαMHCR403Q, in which expression of the HCM-causing Arg403Gln mutation in the α-myosin heavy chain (MHC) gene is inhibited by doxycycline administration. Cardiac structure and function were evaluated in groups of mice that received doxycycline for varying periods from 0 to 40 weeks of age.
  
  
  RESULTS
  Untreated tTAxαMHCR403Q mice showed increased left ventricular (LV) mass, contractile dysfunction, myofibrillar disarray, and fibrosis. In contrast, mice treated with doxycycline from conception to 6 weeks had markedly less LVH and fibrosis at 40 weeks. Transgene inhibition from 6 weeks reduced fibrosis but did not prevent LVH or functional changes. There were no differences in LV parameters at 40 weeks between mice with transgene inhibition from 20 weeks and mice with continuous transgene expression.
  
  
  CONCLUSIONS
  These findings highlight the critical role of the early postnatal period in HCM pathogenesis and suggest that mutant sarcomeres manifest irreversible cardiomyocyte defects that induce LVH. In HCM, mutation-silencing therapies are likely to be ineffective for hypertrophy regression and would have to be administered very early in life to prevent hypertrophy development.
authors: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
authors: Leah
authors: L
authors: Cannon
authors: Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
authors: Ze-Yan
authors: ZY
authors: Yu
authors: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
authors: Tadeusz
authors: T
authors: Marciniec
authors: Cardiac Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
authors: Ashley J
authors: AJ
authors: Waardenberg
authors: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Kensington, Australia.
authors: Siiri E
authors: SE
authors: Iismaa
authors: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Kensington, Australia.
authors: Vesna
authors: V
authors: Nikolova-Krstevski
authors: Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
authors: Elysia
authors: E
authors: Neist
authors: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia.
authors: Monique
authors: M
authors: Ohanian
authors: Anatomical Pathology Department, St. Vincent's Hospital, Darlinghurst, Australia.
authors: Min Ru
authors: MR
authors: Qiu
authors: Anatomical Pathology Department, St. Vincent's Hospital, Darlinghurst, Australia.
authors: Stephen
authors: S
authors: Rainer
authors: Cardiac Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Kensington, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Australia.
authors: Richard P
authors: RP
authors: Harvey
authors: Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Kensington, Australia; Cardiology Department, St. Vincent's Hospital, Darlinghurst, Australia.
authors: Michael P
authors: MP
authors: Feneley
authors: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Kensington, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, Australia; Cardiology Department, St. Vincent's Hospital, Darlinghurst, Australia. Electronic address: b.graham@victorchang.edu.au.
authors: Robert M
authors: RM
authors: Graham
authors: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Kensington, Australia; Cardiology Department, St. Vincent's Hospital, Darlinghurst, Australia. Electronic address: d.fatkin@victorchang.edu.au.
authors: Diane
authors: D
authors: Fatkin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D012518:Sarcomeres / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D012313:RNA; D018995:Myosin Heavy Chains
keywords: genetics; mouse models