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
Journal of Physiology 2006 August 15, 575 (Pt 1): 201-13
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 beta-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.

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