Cardiac hypertrophy is an initial adaptive process in response to a variety of physiological and pathological stimuli. In certain conditions such as chronic hypertension, compensated hypertrophy an lead to congestive heart failure. Previous studies have proposed that abnormal excitation contraction coupling and regulation may be responsible for impaired contractility in failing heart. A number of Ca/2+ handling systems involved in myocardial contraction and the cellular basis for the defect in heart failure is not completely understood. In addition, the correlation between the functional abnormalities and the stages of hypertrophy, including before and during the onset of heart failure, as well as end stage congestive heart failure, has not been well- characterized. Our long term objective is to understand the cellular mechanisms that rigger cardiac hypertrophy and regulate the transition between compensated and decompensated phases of cardiac hypertrophy. This application focuses on cellular mechanisms important for myocardial Ca/2+ homeostasis . We hypothesize that changes in ionic currents and autonomic regulation that are involved in cellular Ca/2+ homeostasis occur in hypertrophied myocardium and that the degree of alteration is dependent upon the severity of hypertrophy and the presence of heart failure. To test this hypothesis, a transgenic mouse model of compensated hypertrophy which exhibits cardiac physiological events observed in animal models and human heart failure with a remarkable recapitulation with biochemical alterations associated with various stages of disease will be determined by patch clamp technique. Once the failure by transferring gene of certain defective components. This research is fundamental to our understanding of cellular mechanisms of cardiac hypertrophy and failure. These studies will not only field significant new information on the basic cellular mechanisms that regulate heart failure, but will also provide new and valuable insights into the design of drugs as well as novel therapeutic approaches for cardiovascular disease.
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