Abstract 155 Cardiology: Mouse Models and Basic Mechanisms of Cardiac Disease Platform, Tuesday, 5/4

Contraction of the heart occurs through regulated interactions of the myofilament proteins in response to increasing intracellular calcium concentrations. Contractile dysfunction associated with myocardial disease is linked to an altered response of the contractile proteins to calcium. Myocardial stunning is a form of ischemic injury which occurs with transient ischemia followed by re-establishment of flow. Clinically it is associated with reversible myocardial systolic and diastolic dysfunction lasting one to several days. The cellular physiology of stunning is marked by diminished force development without a change in the calcium transient and thus a relative insensitivity of the myofilaments to calcium. Recently, we have identified a specific proteolysis of the myofilament protein, troponin I (TnI), which is tightly linked to the stunning phenotype. The proteolysis results in a loss of 17 amino acids from the carboxy terminus of cardiac TnI. In order to determine whether modification of TnI (TnI 1-210) produces a stunned phenotype we created transgenic mice with expression of a truncated cardiac troponin I lacking the 17 carboxy terminal amino acids (TnI 1-193). Three founder mice were bred to produce lines. Analyses of contractile proteins in these lines demonstrated the truncated variant was expressed at low levels, 9-17% of native TnI. The transgene produced a phenotype of a dilated cardiomyopathy. Histological studies demonstrated cellular hypertrophy without myofibrillar disarray. The mice (n=7) were further characterized by measurements of ventricular mechanics using a miniaturized conductance-micromanometer catheter. These studies demonstrated reduced systolic function with decreased dP/dt (TnI 1-193 = 7409 mmHg/sec vs. control 9104 mmHg/sec) and decreased end-systolic elastance (TnI 1-193 14.5 mmHg/ul vs. 23.0 mmHg/ul in control). Steady state force-calcium relationships in isolated trabeculae indicate the transgenic TnI 1-193 muscle had decreased maximal force and a relative insensitivity to calcium. We conclude that the modification of TnI which occurs in myocardial stunning produces the systolic dysfunction and myofilament calcium insensitivity typical of this syndrome. Thus, partial proteolysis of TnI is sufficient to explain the pathogenesis of stunned myocardium.