: The mechanisms responsible for progressive myocardial dysfunction and remodeling of the cardiomyopathic, intact failing human heart are unknown. The mechanism(s) behind Beta-blocker related improvements in myocardial function and reversal of remodeling also remains unknown. In general, the pathophysiologic mechanisms responsible for progressive myocardial failure and remodeling are likely to involve signaling mechanisms, which alter myocardial gene expression. Similarly, the molecular basis for improvement in myocardial function and remodeling following treatment with Beta-blocking agents also is likely due to time-dependent changes in 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 identify, in human subjects with myocardial failure, gene expression profiles associated with changes in myocardial function. This proposal investigates 1) the expression of over 12,000 genes in the failing human heart relative to nonfailing controls 2)changes in gene expression associated with Beta-blocker related improvement in myocardial function. Using microarray analysis we are able to measure the expression of a large number of genes in small quantities of human ventricular myocardium that can be obtained serially from the intact heart by right ventricular (RV) endomyocardial biopsy. We have demonstrated that in situations where left and right ventricular function are concordant, directional changes in gene expression are similar in RV free wall, RV septal endomyocardium, and LV free wall, indicating that RV septal endomyocardial biopsy samples may be used to investigate changes in RV or LV free wall gene expression. Thus, this proposal has the ability to determine the molecular mechanisms responsible for myocyte dysfunction in the intact human heart. Furthermore, this proposal has the ability to provide information relevant to the mechanisms responsible for Beta-blocker-related improvements in myocardial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23HL068875-01A1
Application #
6579141
Study Section
Special Emphasis Panel (ZHL1-CSR-J (O1))
Program Officer
Commarato, Michael
Project Start
2003-09-15
Project End
2008-08-31
Budget Start
2003-09-15
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$130,680
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Lowes, Brian D; Buttrick, Peter M (2008) Genetic determinants of drug response in heart failure. Curr Cardiol Rep 10:176-81
Lowes, Brian D; Zolty, Ronald; Shakar, Simon F et al. (2007) Assist devices fail to reverse patterns of fetal gene expression despite beta-blockers. J Heart Lung Transplant 26:1170-6
Tate 3rd, Charles W; Robertson, Alastair D; Zolty, Ronald et al. (2007) Quality of life and prognosis in heart failure: results of the Beta-Blocker Evaluation of Survival Trial (BEST). J Card Fail 13:732-7
Lowes, Brian D; Zolty, Ronald; Minobe, Wayne A et al. (2006) Serial gene expression profiling in the intact human heart. J Heart Lung Transplant 25:579-88
Rivera, DeeAnn M; Lowes, Brian D (2005) Molecular remodeling in the failing human heart. Curr Heart Fail Rep 2:5-9