MYOCARDIAL RELAXATION AND CA++ TRANSPORT IN HYPERTROPHY

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DESCRIPTION (adapted from the applicant's abstract): The overall goal of the proposed research is to determine the mechanisms that cause impaired relaxation and Ca2+ handling in left ventricular hypertrophy (LVH) and to develop effective therapies to reverse these abnormalities. The applicant addresses three major problems. First, the mechanisms that cause slowing of relaxation, an important element of cardiac dysfunction in LVH, remain uncertain. Slowing of the decline of free cytosolic [Ca2+] ([Ca2+]c) has been reported, suggesting this may be a factor. But there are little data showing a close relationship between relaxation and [Ca2+]c decline that would support causality. Furthermore, [Ca2+]c does not directly indicate the extent to which the contractile proteins are activated by Ca2+. Second, although abnormal activity and content of SR Ca2+-ATPase have been implicated in slowing [Ca2+]c decline in LVH, a close link between [Ca2+]c decline and SR Ca2+-ATPase has not been established. Third, currently available therapies for cardiac dysfunction in LVH are not effective. Preliminary data suggest that thyroid hormone reverses slowed relaxation and [Ca2+]c decline even though treatment was started after pathological LVH was established, and despite continued pressure-overload. To address these issues, three major hypothesis will be tested: 1. Slowing of myocardial relaxation is primarily caused by slowing of the rate of [Ca2+]c decline. 2. Slowing of [Ca2+]c decline is caused by abnormal function and/or levels of SR Ca2+-ATPase. 3. Thyroid hormone accelerates relaxation and [Ca2+]c decline in pathological LVH. Isovolumic hearts (rat) will be used to establish a link between [Ca2+]c (indo-1 fluorescence) and relaxation in LVH (pressure-overload). Muscle strips will be used to determine whether slowing of Ca2+-activation is the fundamental mechanism that slows relaxation in LVH. SR Ca2+ uptake and levels of SR Ca2+-ATPase, and its regulatory protein, phospholamban, will be assessed using myocytes (Western blots).