Stimulation with two adrenergic agonists led to sudden cardiac death in all male but not female mutant mice with cardiac troponin T mutations, suggesting sex-specific altered adrenergic responsiveness.
In mouse models of familial hypertrophic cardiomyopathy, responses to pathological stimuli, including sudden cardiac death from adrenergic stress, are highly dependent on the specific cTnT mutation and sex.
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.
Maass et al. (Tue,) conducted a other in Familial hypertrophic cardiomyopathy. Pathological, pharmacological, hypertrophic stimuli (including adrenergic agonists) vs. Wild-type mice and opposite sex was evaluated on Hypertrophy, fibrosis, and sudden cardiac death. Stimulation with two adrenergic agonists led to sudden cardiac death in all male but not female mutant mice with cardiac troponin T mutations, suggesting sex-specific altered adrenergic responsiveness.
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