Leah Cannon1, Ze-Yan Yu2, Tadeusz Marciniec1, Ashley J Waardenberg3, Siiri E Iismaa4, Vesna Nikolova-Krstevski4, Elysia Neist2, Monique Ohanian1, Min Ru Qiu5, Stephen Rainer5, Richard P Harvey6, Michael P Feneley7, Robert M Graham8, Diane Fatkin9. 1. Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia. 2. Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia. 3. Cardiac Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia. 4. Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Kensington, Australia. 5. Anatomical Pathology Department, St. Vincent's Hospital, Darlinghurst, Australia. 6. 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. 7. 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. 8. 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. 9. 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.
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. OBJECTIVES: 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.
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. OBJECTIVES: 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.
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