Cannon, Leah, Yu, Ze-Yan, Marciniec, Tadeusz, Waardenberg, Ashley J., Iismaa, Siiri E., Nikolova-Krstevski, Vesna, Neist, Elysia, Ohanian, Monique, Qiu, Min Ru, Rainer, Stephen, Harvey, Richard P., Feneley, Michael P., Graham, Robert M., and Fatkin, Diane (2015) Irreversible triggers for hypertrophic cardiomyopathy are established in the early postnatal period. Journal of the American College of Cardiology, 65 (6). pp. 560-569.

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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, tTA x αMHC R403Q , 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 tTA x αMHC R403Q 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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