The mechanisms responsible for progressive myocardial dysfunction and remodeling of the cardiomyopathic, failing human heart are unknown. In general, these pathophysiologic mechanisms are likely to involve signaling mechanisms which alter myocardial gene expression. Numerous recent studies have demonstrated that, in order to be meaningful, gene regulation and expression must be examined in the intact heart. The overall objective of this proposal is to test, in human subjects with myocardial failure, the general hypothesis that compensatory mechanisms activated to support the failing heart ultimately decrease systolic function through signaling alterations in myocardial gene expression, which then leads to chamber remodeling. The proposal 1) tests two specific hypotheses for the molecular basis of systolic dysfunction (myosin heavy chain isoform changes and altered Beta- adrenergic signal transduction), and 2) investigates the roles of four signaling pathways (increased wall stress, increased cardiac alpha1- and Beta-adrenergic drive, and increased activity of the renin-angiotensin system) in effecting changes in these two candidate molecular mechanisms. The 3rd aim of the proposal is to establish the temporal relationship between changes in contractile dysfunction and remodeling. The strategy employed in Aims 1 and 2 is to investigate the right ventricle in human subjects with idiopathic dilated cardiomyopathy (IDC) compared to nonfailing controls without cardiomyopathy, and to study dynamic changes in signaling, gene expression and chamber phenotype in IDC subjects treated with a Beta- blocker or placebo. The primary analysis in Aim 3 is in the left ventricle. We have developed techniques to measure the expression of a large number of target genes in small quantities of human ventricular myocardium that can be obtained serially from the intact heart by right ventricular (RV) endomyocardial biopsy, using reverse transcription-quantitative PCR. We have demonstrated that in situations where left and right ventricular function are concordant, directional changes in gene expression are similar in RV septal endomyocardium, RV free wall and LV free wall, indicating that RV endomyocardial biopsy samples may be used to investigate changes in RV or LV free wall gene expression. We have also developed methods to precisely define chamber phenotypic characteristics of the intact human RV, using magnetic resonance imaging and cardiac catheterization. Finally, we have developed methods to precisely measure the four signaling pathways under investigation. Thus, this proposal has the ability to determine some of the mechanisms likely to be responsible for progression in human myocardial failure.
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