Abstract 14777: Transcription of Select Homeobox Genes Increases in Patients with Heart Failure-Reduced Ejection Fraction Who Have Improvements in Left Ventricular Ejection Fraction on β-blocker Therapy
Introduction: In patients with heart failure-reduced ejection fraction the mechanisms of left ventricular reverse-remodeling in response to β-blocker therapy are not fully understood. We used network analysis of longitudinal myocardial gene expression to identify genes involved in LV reverse remodeling.
Methods: 51 patients with non-ischemic dilated cardiomyopathy and LVEF < 40% underwent endomyocardial biopsy and radionuclide ventriculography at 0, 3, and 12 months of β-blocker therapy with either carvedilol or metoprolol CR/XL. LVEF response was defined as an increase in EF of ≥8% at 12 months or if not available, ≥5% at 3 months. Serial endomyocardial biopsies were taken from the distal right ventricular septum using a percutaneous approach. RNA was extracted and quantified using the Affymetrix HGU133_plus_2 chip. Data were normalized controlling for batch effect and low variance probesets removed. The remaining 16,383 probesets were analyzed using an expression network generated from highly correlated (>0.85) genes. The Wilcoxon signed-rank test was used to determine differences at 3 and 12 months.
Results: There were a total of 33 responders and 18 nonresponders. The expression network contained a subnetwork with 5 HOX mRNAs: HOX2A, 3A, 3B, 4A, and 4B. Baseline expression was not significantly different among any of these genes between responders and non-responders. After 1 year, expression of all of HOX genes was higher in those with a favorable LVEF response on β-blocker therapy compared with non-responders (Figure).
Conclusion: Expression of HOX 2A, 3A, 3B, 4A, and 4B was significantly higher in patients who experienced LV reverse remodeling on β-blocker therapy. HOX 3A and 3B are involved in early embryonic cardiac patterning, and the coordinated increase of early HOX transcription factors in β-blocker responders is intriguing with respect to the well-described myocardial return to a fetal gene program in times of cellular and whole cardiac stress.
- © 2012 by American Heart Association, Inc.