Published Online
on October 4, 2004

A more recent version of this article appeared on October 12, 2004

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Submitted on November 14, 2003
Revised on April 29, 2004
Accepted on April 30, 2004

Hypertrophy, Fibrosis, and Sudden Cardiac Death in Response to Pathological Stimuli in Mice With Mutations in Cardiac Troponin T

Alexander H. Maass MD, Kaori Ikeda ; , Silke Oberdorf-Maass , Sebastian K.G. Maier MD, and Leslie A. Leinwand PhD^*

From the Department of Molecular, Cellular, and Developmental Biology (A.H.M., K.I., S.O.-M., L.A.L.), University of Colorado, Boulder, and the Department of Pharmacology (S.K.G.M.), University of Washington, Seattle. A.H.M. and S.K.G.M. are currently at the Department of Medicine, University of Würzburg, Würzburg, Germany. K.I. is currently at the Department of Pharmacology, University of Washington, Seattle. S.O.-M. is currently at the Department of Pharmacology, University of Würzburg, Würzburg, Germany.

^* To whom correspondence should be addressed. E-mail: leinwand{at}stripe.colorado.edu.

Background--Transgenic mouse models expressing a missense mutation (R92Q) or a splice donor site mutation (trunc) in the cardiac troponin T (cTnT) model familial hypertrophic cardiomyopathy (FHC) in humans. Although males from these strains share the unusual property of having significantly smaller ventricles and cardiac myocytes, they differ with regard to systolic function, fibrosis, and gene expression. Little is known about how these phenotypes affect the responses to additional pathological stimuli.

Methods and Results--We tested the ability of hearts of both sexes of wild-type and mutant mice to respond to defined pathological, pharmacological, hypertrophic stimuli in vivo. Hearts of mutant cTnT models of both sexes were able to undergo hypertrophy in response to at least one stimulus, but the extent differed between the 2 mutants and was sex specific. Interestingly, the trunc-mutant mouse heart was resistant to the development of fibrosis in response to pharmacological stimuli. Stimulation with 2 adrenergic agonists led to sudden cardiac death of all male but not female mutant animals, which suggests altered adrenergic responsiveness in these 2 models of FHC.

Conclusions--Hypertrophic signaling is differentially affected by distinct mutations in cTnT and is sex modified. Hearts can respond with either an augmented hypertrophic and fibrotic response or a diminished hypertrophy and resistance to fibrosis. Sudden cardiac death is related to adrenergic stress and is independent of the development of fibrosis but occurred only in male mice. These results suggest that patients with certain TnT mutations may respond to certain pathological situations with a worsened phenotype.

Key words: cardiomyopathy • catecholamines • death, sudden • hypertrophy • remodeling

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