Abstract 18127: Gene Expression Changes Associated With β-Blocker Reverse Remodeling in the Failing Human Heart Constitute a β1-Adrenergic Receptor Gene Regulatory Network
Background: When β-blocking agents produce reverse remodeling on nonischemic dilated cardiomyopathies (NDCMs) they effect a partial reversal of heart-failure associated changes in expression of constituents of the classic fetal-adult contractile protein (CP)/natriuretic peptide (NP)/SR Ca2+ ATPase (SERCA2a) gene "program". We have also reported that the DCM abnormalities in CPs, SERCA2a and NPs are associated with evidence of hypothyroidism at the thyroid hormone receptor (THR)-α level.
Methods and results: We treated 47 NDCM patients (mean baseline LVEFs 24+9%, RVEFs 27+9%) with β-blockers (metoprolol CR/XL, metoprolol + doxazosin, or carvedilol in a randomized allocation) for 18 months. A total of 37 patients had reverse remodeling responses. mRNA expression from RV septal biopsies at baseline, 3 and 12 months of treatment was assessed by quantitative PCR for 50 prespecified genes, as well as using microarrays that included sequences for 21,700 human genes (Affymetrix HGU133 plus 2.0). The 50 prespecified genes were selected for having fetal or adult expression characteristics, being THR or β1 adrenergic receptor (AR) responsive, or for encoding Gq-coupled, metabolic or cytokine proteins. Using last-observation-carried-forward and non-parametric statistical analysis, 21 genes changed expression in the 37 patients who had reverse remodeling responses compared to the 10 patients who did not. All 21 reverse remodeling-associated genes have been previously described as being regulated by β1-AR signaling. Seventeen (81%) of the 21 changed mRNAs had a previously described fetal-adult pattern, and 72% were THR responsive. Of the changed β1-AR responsive genes, 13/21 were also statistically significant by microarray analysis, with all 21 mRNAs changing in the same direction on the microarray as in the qPCR results.
Conclusion: Myocardial gene expression changes associated with β-blocker reverse remodeling of human NDCMs are most consistent with a β1 adrenergic receptor gene regulatory network. The transcription factors and/or miRs involved in this network remain to be identified.
- © 2013 by American Heart Association, Inc.