During heart failure intracellular [PCr] decreases in species including rats, turkeys, dogs and humans. The goal of this research is to determine the role this decrease in intracellular phosphocreatine concentration [PCr] plays in the pathophysiology of heart failure. To accomplish this, we will establish a strain of transgenic mice that lack a functional creatine transporter and will therefore have a chronically lowered [PCr]. We will compare these [PCr] deficient mice to normal mice with regard to their: 1) morphology, 2) cardiac mechanics, 3) high energy phosphate turnover and 4) metabolic enzymology. This comparison will be made during baseline conditions and also during inotropic stimulation. This will allow us to determine how both baseline cardiac function and cardiac reserve are affected by a chronic decrease in [PCr]. We have chosen this heart failure-associated change in myocyte biochemistry to study because: 1) a lowered intracellular [PCr] appears to be specific to the failing heart, and 2) PCr is the primary high-energy phosphate in the myocardium providing most of the """"""""energy reserve"""""""" for the heart. It is our hypothesis that the decrease in [PCr] observed during heart failure is causally related to the decrease in cardiac function observed in the failing myocardium challenged to perform increased work.
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