Hypertrophic defect unmasked by calcineurin expression in asymptomatic tropomodulin overexpressing transgenic mice

Objective: Dilation and hypertrophy often occur concurrently in cardiomyopa thy, yet the interaction between these two functionally distinct conditions remains unknown. Methods: Combinatorial effects of hypertrophy and dilatio n were investigated by cross-breeding of two cardiomyopathic transgenic mou se lines which develop either hypertrophy (calcineurin-mediated) or dilatio n (tropomodulin-mediated). Results: Altering the intensity of signals drivi ng hypertrophy and dilation in cross-bred litters resulted in novel disease phenotypes different from either parental line. Augmenting the calcineurin -dependent hypertrophic stimulus in tropomodulin overexpressing transgenics elevated heart:body weight ratios, increased ventricular wall thickness, a nd significantly accelerated mortality. These effects were evident in calci neurin cross-breeding to tropomodulin backgrounds of transgene homozygosity (severe dilation) or heterozygosity (mild dilation to asymptomatic). Molec ular analyses indicated that tropomodulin and calcineurin signaling events in the first week after birth were critical for determination of disease ou tcome, substantiated by demonstration that temporary neonatal inhibition of tropomodulin expression prevents dilation. Conclusions: This study shows t hat postnatal timing of altered signaling in cardiomyopathic transgenic mou se models is a pivotal part of determining outcome. In addition, intensifyi ng hypertrophic stimulation exacerbates dilated cardiomyopathy, supporting the concept of shared molecular signaling between hypertrophy and dilation. (C) 2000 Elsevier Science B.V. All rights reserved.