Hypertrophy, fibrosis, and sudden cardiac death in response to pathological stimuli in mice with mutations in cardiac troponin T.
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.


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
Alexander H
AH
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA.
Ikeda
Kaori
K
Oberdorf-Maass
Silke
S
Maier
Sebastian K G
SK
Leinwand
Leslie A
LA
D000316:Adrenergic alpha-Agonists / Q000633:toxicity; D000318:Adrenergic beta-Agonists / Q000633:toxicity; D019943:Amino Acid Substitution; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001835:Body Weight; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size; D010641:Phenotype; D010656:Phenylephrine / Q000633:toxicity; D017354:Point Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012727:Sex Characteristics; D020107:Troponin T / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D020033:Protein Isoforms; D022821:RNA Splice Sites; D012333:RNA, Messenger; D020107:Troponin T; D000804:Angiotensin II; D010656:Phenylephrine; D007545:Isoproterenol