Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy.
The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and a high incidence of sudden death, despite causing little or no cardiac hypertrophy. In skinned fibers, I79N increased myofilamental calcium sensitivity (Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., deFreitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G., and Potter, J. D. (2001) J. Biol. Chem. 276, 3743-3755). To further study the functional consequences of this mutation, we compared the cardiac performance of transgenic mice expressing either human TnT-I79N or human wild-type TnT. In isolated hearts, cardiac function was different depending on the Ca(2+) concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts at 0.5 and 1 mmol/liter. At higher Ca(2+) concentrations, systolic function was not different, but diastolic dysfunction became manifest as increased end-diastolic pressure and time to 90% relaxation. In vivo measurements by echocardiography and Doppler confirmed that base-line systolic function was significantly higher in Tg-I79N mice without evidence for diastolic dysfunction. Inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality in Tg-I79N mice. Doppler studies ruled out aortic outflow obstruction and were consistent with increased chamber stiffness. We conclude that in vivo, the increased myofilament Ca(2+) sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation.
Knollmann
B C
BC
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington, D. C. 20007, USA.
Blatt
S A
SA
Horton
K
K
de Freitas
F
F
Miller
T
T
Bell
M
M
Housmans
P R
PR
Weissman
N J
NJ
Morad
M
M
Potter
J D
JD
D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003198:Computer Simulation; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004562:Electrocardiography; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008943:Mitral Valve / Q000378:metabolism; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D010805:Physical Conditioning, Animal; D013997:Time Factors; D020107:Troponin T / Q000235:genetics*; D018487:Ventricular Dysfunction, Left
D002316:Cardiotonic Agents; D020107:Troponin T; D007545:Isoproterenol; D002118:Calcium