MALADAPTIVE MECHANISMS AND THERAPEUTIC APPROACHES IN HEART FAILURE

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A number of cardiac regulatory responses and gene programs are known to be adaptive in conditions of stress, exercise of cardiac overload but become inadequate or maladaptive when the heart fails. The overall goals of Project 4 are to investigate the pathogenesis of these transitions, focusing on 3 important precursors of the progressive state of heart failure: myocardial cell hypertrophy, alterations in force-frequency relations and their response to adrenergic stimulation, and in myocardial perfusion-contraction relations. The emphasis in this project will be on assessing responses in the whole heart under intact circulatory conditions. To this end, quantitative microangiographic and echocardiographic methods are now available for studying cardiac function in murine, rat and larger animal models of heart failure. These techniques also will allow the in vivo phenotypic characterization of transgenic mice harboring candidate genes developed by project 1 which are known to influence hypertrophy or myocardial dysfunction, such as Ras and beta-MHC mutants. The adaptive or maladaptive role of cardiac hypertrophy will also be studied in experimental heart failure in mice and rats using exogenous administration of growth factors (initially insulin-like growth factor-1 [IGF-1]). The functional significance of impaired force-frequency (FF) relations reported in isolated muscle from failing human hearts will be investigated in the intact failing heart, and in collaboration with Project 3 electrophysiologic and fluorescence studies in isolated cells from these hearts on the functional components of the Ca2+ transport system, particularly the sarcoplasmic reticulum and the Na+/Ca2+ exchanger, will be correlated with measurements of mRNA and proteins and ultrastructural analysis by immunostaining of Ca2+ transport proteins (Project 5). The impaired responsiveness of force-frequency effects, which is markedly enhanced by adrenergic stimulation or exercise under normal conditions, will be investigated, and potential therapeutic approaches (including beta- blockade, and captopril) for improving impaired basal force-frequency relations and adrenergic responsiveness will be explored in an intact heart failure model. Such models also will be combined with fluorescent microsphere technology to also investigate the hypothesis that impaired coronary blood flow regulation, particularly due to increased heart rate at rest or during adrenergic stimulation, can lead to unfavorable perfusion- contraction matching with impaired cardiac function in dilated cardiomyopathy. Finally, a clinical component will initiate studies on force-frequency relations and their response to adrenergic stimulation in patients with dilated cardiomyopathy. These investigation in the intact heart should provide new information on the mechanisms and functional effects of hypertrophy, force-frequency relations and myocardial blood flow in hart failure, laying the basis for future investigations on their clinical significance and potential for therapeutic modification.