Differential effect of troponin T mutations on the inotropic responsiveness of mouse hearts - Role of myofilament Ca2+ sensitivity increase

Syevda G. Sirenko, James D. Potter, Björn C. Knollmann

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Troponin T (TnT) mutations that cause familial hypertrophic cardiomyopathy (FHC) and sudden cardiac death frequently increase myofilament Ca2+ sensitivity, suggesting that their Ca2+-sensitizing effect contributes importantly to the FHC pathogenesis. To test this hypothesis, we compared transgenic mice expressing the Ca2+-sensitizing TnT-I79N mutant (I79N), which causes a high rate of sudden cardiac death in patients, with mice expressing the more benign TnT-R278C mutant (R278C) that does not affect myofilament Ca2+ sensitivity. Acutely increasing myofilament Ca2+ sensitivity with EMD57033 served as a positive control. Isovolumically contracting hearts were compared over a range of loading conditions (Frank-Starling curve). Consistent with their increased myofilament Ca2+ sensitivity, I79N-Tg hearts demonstrated significantly higher systolic performance at low perfusate [Ca2+] compared with R278C-Tg hearts, which were not statistically different from control hearts expressing either human wild-type TnT or no transgene (CON). Diastolic function was impaired in both FHC mutants (time to 90% relaxation: I79N 48 ± 1.0 ms, n = 10 or R278C 47 ± 0.4 ms, n = 7, versus CON 44 ± 1.0 ms, n = 20, P < 0.05). In the presence of isoproterenol, almost all contractile parameters of R278C hearts became indistinguishable from control hearts, whereas both systolic and diastolic function of I79N hearts significantly worsened (end-diastolic pressure: I79N 20 ± 4 mmHg versus CON 13 ± 2 mmHg or R278C 11 ± 2 mmHg, P < 0.05). The Ca2+ sensitizer EMD57033 produced an even greater contractile dysfunction than the I79N mutation at fast pacing rates. In vivo, maximal exercise tolerance was significantly impaired only in I79N mice. Pretreatment with β-adrenergic receptor antagonists abolished differences in exercise tolerance. In conclusion, the Ca2+-sensitizing effects of TnT mutations may reduce the responsiveness of mouse hearts to inotropic stimuli. 2006 The Authors. Journal compilation

Original languageEnglish
Pages (from-to)201-213
Number of pages13
JournalJournal of Physiology
Volume575
Issue number1
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

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Troponin T
Myofibrils
Mutation
Familial Hypertrophic Cardiomyopathy
Exercise Tolerance
Sudden Cardiac Death
Starlings
Adrenergic Antagonists
Transgenes
Isoproterenol
Transgenic Mice
Blood Pressure

ASJC Scopus subject areas

  • Physiology

Cite this

Differential effect of troponin T mutations on the inotropic responsiveness of mouse hearts - Role of myofilament Ca2+ sensitivity increase. / Sirenko, Syevda G.; Potter, James D.; Knollmann, Björn C.

In: Journal of Physiology, Vol. 575, No. 1, 01.08.2006, p. 201-213.

Research output: Contribution to journalArticle

Sirenko, Syevda G. ; Potter, James D. ; Knollmann, Björn C. / Differential effect of troponin T mutations on the inotropic responsiveness of mouse hearts - Role of myofilament Ca2+ sensitivity increase. In: Journal of Physiology. 2006 ; Vol. 575, No. 1. pp. 201-213.
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