Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy
Bc. Knollmann et al., Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy, J BIOL CHEM, 276(13), 2001, pp. 10039-10048
The cardiac troponin T (TnT) 179N mutation has been linked to familial hype
rtrophic cardiomyopathy and a high incidence of sudden death, despite causi
ng little or no cardiac hypertrophy. In skinned fibers, 179N increased myof
ilamental calcium sensitivity (Miller, T,, Szczesna, D,, Housmans, P, Il,,
Zhao, J., deFreitas, F., Gomes, A V., Culbreath, L,, McCue, J,, Wang, Y,, X
u, Y.,Kerrick, W. G., and Potter, J. D, (2001) J, Biol. Chen. 276, 3743-375
5), To further study the functional consequences of this mutation, we compa
red the cardiac performance of transgenic mice expressing either human TnT-
179N or human wild-type TnT. In isolated hearts, cardiac function was diffe
rent depending on the Ca2+ concentration of the perfusate; systolic functio
n was significantly increased in Tg-179N hearts at 0.5 and 1 mmol/liter, At
higher Ca2+ concentrations, systolic function was not different, but diast
olic dysfunction became manifest as increased end-diastolic pressure and ti
me to 90% relaxation, In vivo measurements by echocardiography and Doppler
confirmed that base-line systolic function was significantly higher in Tg-1
79N mice without evidence for diastolic dysfunction. Inotropic stimulation
with isoproterenol resulted only in a modest contractile response but cause
d significant mortality in Tg-179N mice. Doppler studies ruled out aortic o
utflow obstruction and were consistent with increased chamber stiffness. We
conclude that in vivo, the increased myofilament Ca2+ sensitivity due to t
he 179N mutation enhances base-line contractility but leads to cardiac dysf
unction during inotropic stimulation.